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Será que o gene CD38, responsável por libertar oxitocina (também conhecida como hormona do carinho), está relacionado com relacionamentos mais felizes?

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Influência positiva dos genes na obesidade

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Influência positiva dos genes na obesidade

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Variantes de genes podem ajudar a proteger o corpo contra a obesidade

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Pesquisa publicada na Science indica que pessoas com mutações genéticas raras podem ter 54% menos chance de desenvolver a doença

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Influência negativa dos genes na obesidade

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Influência negativa dos genes na obesidade

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Obesidade: ‘Meus genes são programados para acumular gordura’ - BBC News Brasil

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Profissionais de saúde dizem que obesidade deve ser vista como doença complexa e que pessoas que sofrem com excesso de peso não devem ser consideradas culpadas.

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Um estudo realizado na universidade de Cambridge na Inglaterra, com moscas da fruta, permitiu a descoberta de novos genes que contribuem par a obesidade

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Cross trait LD- uso de estatísticas de associação de variantes genéticas em todo o genoma para estimar a correlação genética entre duas características de interesse.
Autosomal Loci- localização de um gene especifico num qualquer cromossoma que não os sexuais.
Taxonic- Qualquer uma das características taxonómicas, como filo ou subespécie.
Binary Variable- são variáveis ​​que assumem apenas dois valores. Por exemplo, masculino ou feminino.
Survey- examinar/pesquisa
Polygenicity- é aquela  cujo fenótipo é influenciado por mais de um gene. As características que exibem uma distribuição contínua, como altura ou cor da pele. Muitas destas também são influenciadas pelo ambiente e são chamadas de multifatoriais.
In silico-é uma expressão usada no âmbito da simulação computacional e áreas correlatas para indicar algo ocorrido em ou através de uma simulação.

S ex hormone-binding globulin (SHBG)- é uma glicoproteína que se liga a hormonas sexuais especificamente à testosterona e ao estradiol, e com eles circula na rede sanguínea.
SNP ou single nucleotide polymorphism- é a variação de uma única base nucleotídica na sequência do DNA. Por exemplo, a substituição de uma citosina (C) por uma guanina (G)

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Kinsey scale- tipo de escala que classifica o indivíduo quanto à sua sexualidade através da análise de determinados comportamentos; recorre a valores do 0 ao 6 em que 0 descreve um “comportamento estritamente heterossexual” e 6 corresponde a um “comportamento estritamente homossexual”

Meta-analysis- método de análise que une e correlaciona os dados e resultados de estudos distintos de modo a responder a uma só questão/problema.

Dataset- conjunto de vários dados num determinado estudo.

Genotyping- técnica que permite a deteção de pequenas diferencias genéticas entre indivíduos que podem, eventualmente, levar a alterações em maior escala no fenótipo da espécie.

Kallmann syndrome- condição médica demarcada pelo atraso da puberdade no indivíduo, bem como um sentido de olfato menos apurado do que o comum. É resultado pelo défice na produção de determinados tipos de hormonas por parte do organismo.

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A genética da obesidade: da descoberta à biologia

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Antes de se responder à nossa questão é preciso primeiro compreender o que é a oxitocina. Para isso, temos como recurso este artigo que vai explicar um pouco o que é a oxitocina e algumas das suas funções.

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A ocitocina é um hormônio produzido no cérebro, que tem papel importante para facilitar o parto e a amamentação, mas também pode ser encontrada em farmácias, na forma de cápsulas, líquida ou em spray, como é o caso do Syntocinon, por exemplo, devendo ser utilizada somente segundo orientação médica.

Ela também é conhecida como hormônio do amor, devido ao seu papel para a melhora do humor, da interação social, diminuição da ansiedade e aumento da ligação entre parceiros. No homem, este hormônio é capaz de diminuir a agressividade, deixando-o mais mais amável, generoso e social, embora sua atuação seja muitas vezes bloqueada pela ação da testosterona. Saiba mais sobre os efeitos da ocitocina no homem.

As principais funções da ocitocina no organismo são:

1. Facilitar o parto

Devido a sua estimulação para a contração do útero, de forma ritmada, a ocitocina naturalmente produzida pelo corpo ajuda o trabalho de parto. No entanto, em forma de medicamento, ela é utilizada quando é preciso induzir o parto, em grávidas cujo parto não aconteceu no tempo previsto, como as com mais de 41 semanas de gestação ou quando está muito demorado.

Ela só deve ser utilizada com a indicação do obstetra, não podendo ser utilizada em outras ocasiões por mulheres grávidas, devido ao risco de abordo ou parto prematuro.

2. Auxiliar a amamentação

A ocitocina é produzida naturalmente pelo corpo da mulher, devido ao estímulo de sucção do bebê durante a amamentação. O hormônio sintético vendido em farmácias pode ser utilizada de 2 a 5 minutos antes de cada mamada ou antes da retirada do leite com a bombinha, se a mulher tiver dificuldades em amamentar ou se for mãe adotiva, auxiliando a amamentação e a ligação entre mãe e filho.

3. Melhorar as relações sociais

A ocitocina tem papel na melhora do convívio social, na percepção das expressões emocionais e sensibilidade, portanto, este hormônio parece ter efeitos positivos para ajudar no tratamento de pacientes com autismo e esquizofrenia, em casos indicados pelo psiquiatra.

4. Ajudar a combater a depressão e ansiedade

Este hormônio pode adequar a expressão das emoções, diminuindo a sensação de estresse, além melhorar o humor e o convívio com as pessoas, podendo, em alguns casos, auxiliar o tratamento de pessoas com depressão, ansiedade intensa e com fobia social. Nestes casos, o uso da ocitocina também deve ser indicado pelo psiquiatra.

5. Aumentar o prazer no contato íntimo

Acredita-se que a ocitocina tem função na melhora da libido e do desempenho sexual, agindo em conjunto com a testosterona, no homem, e a progesterona, na mulher, para a melhora do prazer e do interesse no contato íntimo, além de facilitar a lubrificação vaginal e o alcance do orgasmo.

O contato físico, não somente sexual, mas também através de abraços e carinhos são formas de aumentar a ocitocina sem precisar de remédios. Veja outras formas de aumentar a ocitocina naturalmente.

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A ocitocina é um hormônio produzido no cérebro, que tem papel importante para facilitar o parto e a amamentação, mas também pode ser encontrada em farmácias, na forma de cápsulas, líquida ou em spray, como é o caso do Syntocinon, por exemplo, devendo ser utilizada somente segundo orientação médica.

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1. Será a doença de Huntington apenas genética?
2. Quanto tempo têm as pessoas depois de sentiremos primeiros sintomas da doença?
3. Existem doenças associadas à doença de Huntington?
4. Há formas de amenizar os sintomas?

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https://www.youtube.com/watch?v=Pr-Bwq-ndjo&ab_channel=Whatmakesittick%3F

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The Genetics of Love │How Love Makes Us Human with Dr Anna Machin

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O gene CD38 ao comandar a libertação de oxitocina vai afetar os relacionamentos, uma vez que, tal como esta investigação nos explica, caso esse gene sofra uma mutação pode estar relacionado com o autismo, uma doença que afeta como uma pessoa se liga a outra. https://www.nature.com/articles/npp2011333

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INTRODUCTION

The neuropeptide oxytocin (OT) has been implicated in a broad range of social processes and behavior ( Meyer-Lindenberg et al, 2011). Studies on healthy humans eg revealed that OT improves mind reading ( Domes et al, 2007b), increases fixation of the eye region ( Guastella et al, 2008), promotes trust ( Kosfeld et al, 2005), in-group favoritism ( De Dreu et al, 2010, 2011), and positive communication during couple conflicts ( Ditzen et al, 2009). It also has diminishing effects on negative social emotions like social stress or anxiety ( Ditzen et al, 2009; Guastella et al, 2009; Heinrichs et al, 2003). Altogether OT seems to serve the continued propagation of the species ( Lee et al, 2009).

Additionally, OT has been implicated in states of aberrant social functioning like in autism spectrum disorders (ASD). Indeed, first attempts to improve social deficits in ASD via OT administration revealed positive results: improved retention of affective speech comprehension ( Hollander et al, 2007), enhanced mind-reading performance ( Guastella et al, 2010), more frequent engagement in positive social interactions, and enhanced feelings of trust and preference towards partners within positive interactions ( Andari et al, 2010).

On a neuronal level, the amygdala seems to have an important role in mediating the effects of OT on social and emotional processing. The amygdala contains a high density of OT receptors ( Huber et al, 2005); moreover several functional magnetic resonance imaging (fMRI) studies revealed OT induced decreases of amygdala activation during social or fear processing ( Baumgartner et al, 2008; Domes et al, 2007a; Kirsch et al, 2005; Petrovic et al, 2008). Although most fMRI studies on OT published so far focus on the amygdala, there are other potentially interesting brain areas like the fusiform gyrus which are also involved in processing of social stimuli. The fusiform gyrus is highly relevant for face perception ( Haxby et al, 2000, 2002; Kanwisher and Yovel, 2006) and is directly connected to the amygdala via reciprocal projections ( Freese and Amaral, 2005, 2006). Interestingly, one OT challenge study also revealed OT induced decreases in activation of the fusiform gyrus ( Petrovic et al, 2008).

As complex neuropsychiatric disorders like ASD as well as many circumscribed psychological functions are highly heritable, approaches that try to bridge the gap between genetics and observable phenotypes have become very popular. One promising attempt is the investigation of 'intermediate phenotypes' via imaging genetics studies ( Meyer-Lindenberg and Weinberger, 2006). Several studies revealed associations between ASD and different single nucleotide polymorphisms (SNPs) on the OT receptor gene ( Gregory et al, 2009; Jacob et al, 2007; Lerer et al, 2008; Wermter et al, 2010; Wu et al, 2005; Yrigollen et al, 2008). However, the relevance and mechanisms of particular SNPs for the ASD phenotype remain largely unclear. The same is true for the influence of these common variants on brain activation, structure or connectivity in healthy humans. Although evidence has been provided for an intermediate phenotype related to one of these receptor gene variations ( rs53576) ( Tost et al, 2010), so far there is no study that has concentrated on other aspects of the OT system like OT production, storage, or secretion. Recently, the transmembrane protein CD38 has received particular attention as it is engaged in OT secretion in the central nervous system and influences social behavior. CD38−/− knockout mice show deficits in social memory processes and maternal nurturing behavior ( Higashida et al, 2010; Jin et al, 2007). Moreover, two recent studies revealed an association between a common variation in the CD38 gene and ASD in a sample of 252 white US families ( Munesue et al, 2010) and in a sample of 149 Israeli Jewish families ( Lerer et al, 2010): rs3796863 with the C-allele as the risk allele. Additionally, the C-allele was found to be associated with lower CD38 expression in lymphoblastoid cells ( Lerer et al, 2010).

In the present study we addressed the question if this genetic variant affects brain activation and behavior during basal social perception processes. Furthermore, we extended the imaging genetics approach by investigating how the effect of a pharmacological challenge with OT is influenced by this CD38 gene variant. This procedure enabled us to detect potential interactions between OT availability and dispositions. As ASD studies have mainly reported hypoactivation of amygdala and fusiform areas in patients ( Jemel et al, 2006; Schultz, 2005; Verhoeven et al, 2010), we expected reduced activation in both structures in homozygotic carriers of the autism-associated C-allele during processing of social stimuli. Under OT we expected a more pronounced effect in homozygotic C-allele carriers because they potentially suffer from a less effective OT system.

MATERIALS AND METHODS

Participants

We investigated 56 healthy young men with no history of psychiatric or neurological illness. All were non-smokers or smoked only occasionally and, except for one, were right-handed. One participant was excluded after completion of the study because he reported afterwards that he had donated plasma in the morning of the first session. Accordingly, the final sample consisted of 55 males; 30 subjects were homozygotic carriers of the risk allele (CC) with respect to rs3796863, 23 were heterozygotes (CA), and 2 were homozygotic carriers of the protective allele (AA). According to the PubMed database, CC and AC are common genetic variants occurring in ∼50 and 46% of the Caucasian population, whereas only 4% are AA carriers ( http://www.ncbi.nlm.nih.gov/projects/SNP). For statistical analyses, we compared a combined group of CA and AA genotypes (A+, the 'lower risk group') with CC carriers (A−, the 'higher risk group'). Groups did not differ in age, education, or order of substance application, although group assignment was performed post hoc according to genotype ( Table 1).

Table 1 Sample Characteristics

The study was approved by the ethics committee of the German Psychological Society (DGPs) and all participants gave written informed consent.

Experimental Design and Procedure

fMRI data were acquired in a double-blind placebo-controlled crossover design. Participants attended two sessions scheduled at the same time of day with an interval of 1 week. For each session, they were asked to abstain from alcohol and cigarettes for 12 h before the experiment and from caffeine for 3 h.

In the first session, participants were first asked to complete a screening questionnaire concerning actual somatic illnesses and the Symptom Checklist 90-R ( Franke, 2002) for a broad range of psychological problems. Afterwards, in each session participants received either placebo (PLA) or a dose of 25 IU of OT (Syntocinon Spray, Novartis, Austria) via intranasal application around 30 min before the start of the first fMRI experiment. Participants administered the substance themselves under observation of the investigator. In total, they administered five puffs alternating nostrils with each puff containing 5 IU. To control for substance effects on mood, arousal dominance, anxiety, anger, and wakefulness, participants completed the following questionnaires before substance administration and after the fMRI session: the Self Assessment Maniquin (SAM) ( Bradley and Lang, 1994), the Multidimensional Mood State Questionnaire (MDBF) ( Steyer et al, 1997), and the state components of the State-Trait Anger Expression Inventory ( Schwenkmezger et al, 1992), and the State-Trait Anxiety Inventory ( Laux et al, 1981).

Before the fMRI session, a 5-min structural MRI scan was performed to obtain anatomical data. Subsequently, we applied two different fMRI tasks, each implying functions of social cognition, which are highly relevant for ASD as well as for OT research: (1) processing of social emotional stimuli and (2) gaze processing (see Supplementary Figure S1 for experimental procedure and example trials of both tasks). The first paradigm was an extended version of the Hariri face matching task ( Hariri et al, 2002b), which we also used in our previous study ( Kirsch et al, 2005) and which has been consistently shown to elicit activation of amygdala as well as fusiform areas ( Hariri et al, 2002a,  2002b, 2003). Participants are required to match one of two simultaneously presented pictures with an identical target. The extended version consisted of blocks showing geometric shapes (control condition) or pictures of faces or scenes with either positive or negative valence (social emotional conditions). Facial stimuli for the matching paradigm were taken from the Ekman and Friesen series (1976) and consisted of angry/fearful faces (negative faces) or happy faces (positive faces). Pictures of social scenes were taken from the International Affective Picture System ( Lang et al, 2008). Negative scenes depicted fear-eliciting social interactions, eg one person threatening another one with a weapon, whereas positive scenes depicted couples in an erotic interaction. Each control task block lasted for 15 s and consisted of six matching trials à 2.5 s, whereas each social-emotional task block had a duration of 30 s with six matching trials à 5 s. There was no interval between the offset of one trial and the onset of the next one, and the stimulus duration was independent of the participant's response. The participant's response was recorded during the trial duration of 5 s. Altogether, every social-emotional task block (negative scenes, positive scenes, negative faces, and positive faces) was presented four times in a non-randomized order and was followed by a control task block each time. Accordingly, the total duration of the matching paradigm was about 13 min.

The second paradigm on gaze processing was used because direct eye gaze is often avoided by ASD patients and the amygdala has been implicated in the processing of gaze direction ( Itier and Batty, 2009; Kawashima et al, 1999). It was applied ∼44 min after OT application and was realized within an event-related design. One trial consisted of a picture of a person with either direct or averted eye gaze and participants were asked to indicate via button press whether the person looked to the left, to the right, or directly to the participant. Stimulus presentation was randomized and lasted for 3 s, independent of the participant's response, with a mean interstimulus interval (offset of a stimulus to onset of the next one) of 5 s. During the interstimulus interval a fixation cross was presented. The participant's response was recorded during stimulus presentation and adjacent interstimulus interval until the onset of the next stimulus. In total, the second experiment consisted of 64 trials, 32 with direct eye gaze and 32 with averted eye gaze (16 left and 16 right). Persons shown on the photos were of mixed gender (eight male and eight female) and age (20-60 years).

fMRI Data Acquisition

Scanning was performed on a 3T Siemens TRIO scanner with the following parameters for the functional MRI scans using EPI sequences: 30 axial slices à 4 mm, 1 mm gap, TR=2 s, TE=30 ms, FoV 192 × 192 mm, and flip angle 80°. Anatomical data were obtained from a T1-weighted three-dimensional MPRAGE sequence (192 sagittal slices of 1 mm thickness, TR=2.3 s, TE=3.03 ms, FoV 256 × 256 mm, and flip angle 9°).

fMRI Data Analyses

fMRI data analysis was conducted by means of SPM8 ( http://www.fil.ion.ucl.ac.uk/spm). Preprocessing procedures were identical for both paradigms. Images were realigned to the first image, slice-time corrected, spatially normalized into a standard stereotactic space with a voxel size of 2 × 2 × 2 mm using the Montreal Neurological Institute template and smoothed with an 8 mm full width at half maximum Gaussian kernel.

On the first level, a general linear model (GLM) incorporating both substance conditions (PLA, and OT) as separate sessions was applied for each paradigm. For each session, task regressors as well as regressors for the six motion parameters from realignment were included in the model, five task regressors for the matching task (one for each experimental condition: forms, negative faces, positive faces, negative scenes, and positive scenes) and two task regressors for the gaze processing task (direct gaze and averted gaze). First level contrasts were defined for both substance conditions combined (OT+PLA) as well as separately (OT and PLA) and for the comparison between substances (OT vs PLA).

To enable us to investigate general aspects of social vs non-social processing as well as more specific aspects of social processing we also specified different kinds of contrasts depending on task condition: for the matching task, we defined one contrast comparing all social conditions to the control condition ('social>non-social') as well as each social condition separately to the control condition ('negative faces>non-social', 'positive faces>non-social', 'negative scenes>non-social', and 'positive scenes>non-social'). Contrasts for the gaze processing task were defined as 'direct+averted>low-level baseline' and 'averted>direct' and 'direct>averted'. Finally, when combining these task conditions with the substance conditions specified above, we eg defined the following first level contrasts for the investigation of general social processing in the first paradigm: 'social>non-social' (PLA), 'social>non-social' (OT), 'social>non-social' (OT+PLA), and 'social>non-social' (OT vs PLA).

In subsequent second level analyses, the two genotypes were compared with two sample t-tests (A− (CC genotype) vs A+ allele (genotypes AA and AC)) based on the contrasts resulting from first level analyses. Additionally, substance order was entered as a covariate of no interest to control for potential influences, because group assignment was performed post hoc based on participants' genotype (though order did not differ between genotype groups). For results presented in the paper, significance threshold was set to p<0.05 corrected for multiple comparisons using Family Wise Error (FWE) correction for the whole brain analyses as well as for Region of Interest (ROI) analyses conducted for the amygdala and the fusiform gyrus. Both ROIs were anatomically defined (Anatomical Automatic Labeling) masks provided by the Wake Forest University PickAtlas software ( http://fmri.wfubmc.edu). This software implemented in SPM 8 runs ROI analyses voxel by voxel and corrects for the number of voxels within the particular mask. For further exploration of the data we also performed the whole brain analyses at a more liberal significance threshold of p<0.001 uncorrected. Results from these analyses can be found in the Supplementary Information ( Supplementary Table S1). For all analyses an additional cluster size threshold was set to a minimum of k=10 contiguously activated voxels.

Behavioral Data Analyses

Behavioral data in terms of reaction times (RT) and correct responses were analyzed using GLM 2 × 2 × 2 repeated measures procedures implemented in PASW Statistics 18 (SPSS, Chicago, IL). Models consisted of task (matching task: social vs non-social; gaze processing task: averted vs direct) and substance conditions (OT vs PLA) as within-subject factors, allele (A− vs A+) as between-subject factor and substance order as a covariate of no interest. For analyses of RT we used the individual person's median rather than the mean because the median is much more robust against outliers. Subsequently, within the GLM, mean values were calculated across individuals' median RT.

Self-reported mood, arousal and so on were analyzed in a similar way by means of 2 × 2 repeated measure analyses of variance, consisting of difference scores (pre vs post substance application) for each substance condition as within subject factor, genotype as between subject factor, and order of substance application as a covariate of no interest.

Genotyping Procedures

DNA was extracted from the buccal cells to avoid a selective exclusion of subjects with blood and injection phobia. Genotyping of the CD38 SNP ( rs3796863) was performed by real-time polymerase chain reaction using a fluorescence melting curve detection analysis (for details see Supplementary Materials and Methods).

RESULTS

Influence of OT and Genotype on Subjective Ratings of Mood, Arousal and so on

Analyses of subjective ratings revealed only two significant results. Firstly, comparing differences between participants' subjective ratings pre and post substance application for both substance conditions resulted in a significant main effect of substance condition for the mood scale of the SAM ( Bradley and Lang, 1994): F(1, 50)=4.144, p=0.047. Although participants reported a slightly reduced positive mood under PLA, the opposite was true for the OT condition where they reported a minimal increase in positive mood.

Secondly, we found an interaction between genotype and substance for the wakefulness scale of the MDBF ( Steyer et al, 1997): F(1, 51)=8.845, p=0.004. Although there was a general increase of fatigue for the whole sample, A+ carriers reported a smaller increase of fatigue from pre to post application under OT compared with PLA. No such effect could be detected in A− carriers.

For none of the other measures a significant main effect of substance or genotype occurred. After applying correction for multiple comparisons (altogether eight individual models (one for each rating scale), therefore α corr=0.05/8=0.00625), only the second result survived.

Task Performance: Median RT and Accuracy

Matching task

Analyses of median RTs in the matching task revealed a significant main effect of task condition (F(1, 52)=165.3, p<0.001). Participants responded faster to non-social forms than to social stimuli. Genotype groups differed significantly regarding RTs (main effect of genotype: F(1, 52)=4.4, p=0.041) with A− carriers showing slower RT than A+.

Moreover, we found interaction effects between factors. Firstly, there was a trend for an interaction between task condition and genotype (F(1, 52)=3.202, p=0.079). Post hoc tests indicate a difference between allele groups only for social ( p=0.040) but not for non-social stimuli ( p=0.121) with A− carriers being slower than A+ ( Figure 1a). Secondly, we found another trend for an interaction between substance condition and A− allele (F(1, 52)=3.979, p=0.051). According to post hoc tests OT led to a reduction of RT in A− carriers ( p=0.032), but not in A+ ( p=0.489). Moreover, genotype groups differed under PLA ( p=0.010) but not under OT ( p=0.190) ( Figure 1b).

Median RT and SD in the matching paradigm. (a) Interaction effect of task condition and genotype for both substance conditions combined. (b) Interaction effect of substance condition and genotype for both task conditions combined. *Indicates significant differences according to post hoc tests ( p<0.05).

PowerPoint slide

Regarding accuracy in terms of percent correct responses, we could only find a main effect of task condition with a better performance for social stimuli than for non-social forms (F(1, 52)=23.583, p<0.001). Moreover, there was a trend for an interaction between task condition and substance order (F(1, 52)=4.039, p=0.050). Participants who received OT in the second session showed a bigger difference between the number of correct responses in both task conditions ( p<0.001) than those participants who received OT in the first session ( p=0.051). But as the task was very easy, we could observe a strong ceiling effect ( Table 2).

Table 2 Reaction Times (RT, Median±SD) and Accuracy (mean percent correct responses±SD) for (A) the matching task and (B) the gaze processing task for both substance conditions

Gaze processing task

With respect to the gaze processing task, neither analyses of RTs nor of percent correct responses yielded significant results (for details on RT and accuracy see Table 2).

Brain Activation

General Processing of Social vs Non-Social Stimuli

Matching task (contrast 'social>non-social')

In general, processing of social stimuli compared with non-social forms led to a widespread activation of visual and limbic brain regions, among these amygdala and fusiform gyrus bilaterally ( p<0.05 FWE-corrected).

Comparison of allele groups (A−>A+) for processing of social stimuli compared with non-social forms during both substance conditions combined (OT+PLA) resulted in one single cluster located in the left fusiform gyrus, which was more highly activated in A− carriers ( k=42, (−20, −32, −18), t=5.62, p=0.012 FWE-corrected) ( Figure 2).

Voxels of the fusiform gyrus with increased activation in the A− group for the contrast 'social>non-social' (both substance conditions combined) superimposed on an inflated standard brain. Display thresholded at p<0.05 FWE-corrected for the whole brain. Note that the image was not masked and there were no voxels outside the fusiform gyrus found significantly activated.

PowerPoint slide

Investigation of both substance conditions separately showed that the fusiform cluster was more highly activated in A− mainly under OT ( k=57, (−30, −40, −20), t=6.21, p=0.002 FWE-corrected) but not under PLA ( Figure 3). However, the difference contrast (OT>PLA) did not reveal significant differences between substance conditions at a significance threshold of p<0.05 FWE-corrected, neither in the whole brain nor in ROI analyses using a fusiform gyrus mask.

Mean contrast estimates±SEM for the left fusiform gyrus peak voxel of the contrast 'social>non-social' (both substance conditions combined) in the matching paradigm. *Indicates significant differences ( p<0.05 FWE-corrected for the ROI).

PowerPoint slide

The reversed allelic contrast (A+>A−) did not produce significant results for substance conditions combined, for separate conditions, or for the comparison of conditions. ROI analyses of amygdala activation did not reveal significant results either.

Gaze processing task (contrast 'direct+averted>low-level baseline')

Processing of facial stimuli compared with a low level baseline in the gaze processing task led to a widespread activation of visual and other face-processing areas, which included strong activation of fusiform gyri and moderate activation of more lateral parts of the amygdala.

To confirm our results of higher fusiform activation in A− carriers in a second data set, we performed ROI analyses for the fusiform gyri in the gaze processing task. We found a significantly increased left fusiform activation for A− carriers compared with A+ during processing of facial stimuli in both substance conditions combined (OT+PLA) in a cluster very similar to that of the matching task ( k=71, (−28, −42, −16), t=4.78, p=0.003 FWE-corrected for the ROI (see Supplementary Figure S2 for illustration of the overlap). Analyzing both substance conditions separately led to a higher activation for A− carriers compared with A+ under OT ( k=27, (−30, −44, −16), t=4.26, p=0.015 FWE-corrected for the ROI) but not under PLA. Again, the statistical comparison (OT vs PLA) yielded no significant result. ROI analyses of amygdala or right fusiform gyrus did not lead to significant results in any of the contrasts either.

Specific Aspects of Social Processing

Besides these effects on general processing of social stimuli, we also investigated more specific aspects of social processing.

Matching task (contrasts 'negative faces>non-social', 'positive faces>non-social', 'negative scenes>non-social', and 'positive scenes>non-social'): Analyzing each social condition of the matching task separately resulted in brain activation patterns comparable to that of the combined contrast 'social>non-social' with strong bilateral amygdala and fusiform gyrus activation ( p<0.05 FWE-corrected).

Genotype effects in the single conditions were also comparable to those of the combined contrast. A− carriers showed stronger activation in the left fusiform gyrus in each of the social task conditions (compared with the non-social forms) combining both substance conditions (OT+PLA, p<0.05 FWE-corrected for the ROI). Although under PLA, there were either no or only small clusters higher activated in the A− group, this allele effect was much stronger under OT ( p<0.05 FWE-corrected for the ROI) ( Supplementary Table S2). None of the statistical comparisons using the difference contrasts OT vs PLA survived FWE-correction procedures for multiple testing. ROI analyses of right fusiform gyrus or amygdala also did not detect any differences between genotypes in the single conditions contrasts.

Gaze processing task (contrasts 'direct>averted' and 'averted>direct'): In the whole sample, analyses of both substance conditions combined (OT+PLA) revealed only a single cluster in the right dorsolateral prefrontal cortex ( k=19, (56, 34, 14), t=5.6, p=0.012 FWE-corrected), which showed higher activation during processing of direct gaze compared with averted gaze. Whereas the opposite contrast 'averted>direct' led to a stronger activation in the left premotor cortex ( k=98, (−24, −8, 56), t=6.27, p=0.001 FWE-corrected).

Comparing genotypes during processing of direct vs averted gaze did not result in different activation patterns in fusiform gyri in both substance conditions combined (OT+PLA), nor separately (OT and PLA) or in their comparison (OT vs PLA). With regard to amygdala activation, we found a significantly higher activation of the amygdala bilaterally in A+ carriers compared with A− for both substance conditions combined (OT+PLA, left cluster: k=38, (−18, −4, −14), t=4.26, p=0.002 FWE-corrected for the ROI; right cluster: k=10, (20, 0, −12), t=3.37, p=0.019 FWE-corrected for the ROI). Analyzing both substance conditions separately, this difference could not be observed under PLA, but only in the left amygdala under OT ( k=37, (−18, −2, −18), t=3.49, p=0.014 FWE-corrected for the ROI) ( Figure 4). However, the statistical comparison of OT vs PLA yielded no significant results.

Mean contrast estimates±SEM for the left amygdala peak voxel of the contrast 'direct>averted' (both substance conditions combined) in the gaze processing paradigm. *Indicates significant differences ( p<0.05 FWE-corrected for the ROI).

PowerPoint slide

DISCUSSION

Our findings provide evidence that rs3796863 impacts social processing on a very basic level. Participants homozygote for the ASD risk allele (A−, genotype CC) showed a locally specific greater activation of left fusiform gyrus during social processing in two independent paradigms. As this effect was observable during processing of emotional and neutral facial stimuli as well as social scenes, it seems not to be restricted to emotion or facial perception but to be a general mechanism taking effect during the processing of social stimuli. Previous studies on face processing in ASD often reported hypoactivation of fusiform gyri, so we originally also had expected the higher risk group (A−) to show hypoactivation of fusiform gyri ( Jemel et al, 2006; Schultz, 2005). However, there is evidence that fusiform activation increases with longer fixation of the eye region in patients, first degree relatives and also in healthy individuals ( Dalton et al, 2005, 2007; Morris et al, 2007). Given that usually patients and relatives exhibit shorter eye fixation times, which lead to hypoactivation of fusiform areas, one could hypothesize that they would revert to normal or even hyperactivation if they exhibited 'normal' scanpaths. In our study all subjects were healthy individuals and hence probably do not show any serious alterations of visual scanning paths like ASD patients do. Accordingly, the increased neural activity in fusiform gyrus together with longer RT indicates a less efficient basal visual social processing system in the higher risk group. It seems possible that in case of ASD that this less efficient system cannot be compensated through increased activation and may result in a breakdown of the system leading to deficits in social processing. Of course, there are other possible explanations for the increased fusiform activation. Eg one could argue that the increased activation derives from reduced habituation to social stimuli in homozygotic risk-allele carriers. In fact it could be shown that in ASD patients amygdala habituation to facial stimuli is reduced ( Kleinhans et al, 2009). However, this was not found for fusiform gyrus where patients and controls did not differ regarding habituation ( Kleinhans et al, 2009). Therefore, this still remains unclear. Another point to be discussed is that differences in behavior (RT) could account for differences in fMRI data. But as we only found behavioral differences in one of the two paradigms and moreover stimulus presentation times were independent from subjects' responses we don't believe behavioral differences to explain our fMRI results.

So far, we can only speculate how the homozygotic occurance of the risk allele may lead to stronger fusiform activation. As the C allele was found to be associated with lower CD38 expression in lymphoblastoid cells in ASD patients ( Lerer et al, 2010) and lower CD38 expression to result in reduced OT secretion ( Jin et al, 2007) it is not clear how reduced OT secretion results in higher fusiform activation. So far, in humans and primates there is no evidence that the fusiform gyrus could be a potential direct target of OT in terms of existing OT receptors ( Loup et al, 1991; Schorscher-Petcu et al, 2009). Therefore, it could be speculated that OT probably affects fusiform activation via so far unknown mechanisms, perhaps via interacting with other neurotransmitter systems like eg the dopamine system. The dopamine system is supposed to have a crucial role for rewarding social affiliative behaviors (which are in turn regulated by OT) and could thereby contribute to ASD's social disinterest and deficits ( Baskerville and Douglas, 2010; Skuse and Gallagher, 2009). This idea is compatible with a model of the pathophysiology of autism ( Schultz, 2005) stating that alterations in the amygdala-fusiform system are the critical neurobiological mechanism underlying ASD's deficits in face perception. A congenital abnormality of the amygdala and the closely connected dopaminergic reward system would then lead to a failure to orient to salient social stimuli such as faces, thereby preventing the development of facial expertize, which is represented in fusiform functioning. As the amygdala seems to be a potential target of OT ( Baumgartner et al, 2008; Domes et al, 2007a; Kirsch et al, 2005; Petrovic et al, 2008), this reduced salience signaling of amygdala to social stimuli could be caused by alterations in the OT system.

However, as we only investigated healthy individuals, it is not possible to transfer that model ( Schultz, 2005) on a one-to-one basis. Especially, our results do not provide any evidence for genotype-dependent alterations in amygdala activation during basal social processing. Nevertheless, it could be speculated that risk allele carriers exhibit aberrant development of their amygdala-fusiform system during childhood and adolescence and that these alterations finally result in a less efficient system in adulthood.

Regarding interactions within the OT system it seems likely that in the initial state reduced OT secretion in the higher risk group leads to an upregulation of OT receptor density and sensitivity resulting in an hypersensitivity to OT as it has already been described for other neurotransmitter systems for a long time ( Burt et al, 1977). Experimentally elevated OT levels could then induce an increased activation of the OT system especially in homozygotic risk-allele carriers and finally lead to even stronger fusiform activation and improved behavioral performance as reported in the present study. However, one should keep in mind that acceleration of RT was not specific for social processing, but was also found in processing of non-social forms, which indicates a general facilitation of visual processing instead of a specific social facilitation effect under elevated OT levels. None of the previous studies on therapeutic effects of OT in ASD patients investigated whether improved performances were specific for social processing or if they also occur during non-social cognitive tasks ( Andari et al, 2010; Guastella et al, 2010; Hollander et al, 2007). Therefore, this question requires further investigation.

With respect to the amygdala we did not find any differences in activation during basal social processing depending on allelic makeup. We also were not able to confirm former results showing increased amygdala activation under direct gaze compared with averted gaze in the whole group ( Kawashima et al, 1999). However, recent evidence suggests that the amygdala response to gaze direction is dependent on different factors like the viewer's anxiety level and besides, these effects strongly differ with respect to different subnuclei of the amygdala ( Ewbank et al, 2010; Hoffman et al, 2007; Straube et al, 2010). Therefore, our result of increased amygdala activation in the A+ group under OT adds to evidence for an additional OT level and genotype-dependent reactivity of the amygdala to direct vs averted gaze.

There are some shortcomings of our study. Firstly, we did not implement a face localizer task to identify individual localization of fusiform face area. Accordingly, we cannot infer if the effect is specific for face processing or rather an effect of processing of complex visual stimuli. Secondly, one has to keep in mind the multiple comparisons problem, which usually occurs in fMRI studies and is as yet unresolved. We performed lots of tests and our study's design would have allowed to perform numerous other tests because of the high number of possible combinations of regressors. But in order to avoid further complexity, we decided to concentrate on those contrasts described above. Lastly, we had only two homozygous risk-allele carriers in our sample and thus cannot conclude anything about gene-dose-effects, which might be present. All these points strongly emphasize the need for further exploration of our results in a replication dataset.

Altogether our study identified alterations in left fusiform gyrus activation as a potential brain mechanism through which the risk variant of rs3796863 could contribute to ASD's social deficits. We also found OT to enhance fusiform activation differences between allele groups and to improve RT only in the higher risk group, thereby clearly supporting the idea of treating ASD patients with OT. However, one has to keep in mind that the risk variant of rs3796863 (A−) is not rare at all with ∼50% occurrence in the Caucasian population. Accordingly, the reported imaging phenotype is also very common and cannot explain the profound social deficits found in ASD patients. Therefore, we rather believe it to be one among lots of different mechanisms involved in deviant social processing in ASD. Correspondingly, any potential therapeutic effect of OT on social functioning in ASD is only partially mediated by the reported imaging phenotype or the underlying genotype. Apart from these constraints, very recently it has been shown that retinoids can be used to increase CD38 expression ( Riebold et al, 2011) implicating a direct method to influence the CD38 system and related social cognitive deficits in autism ( Ebstein et al, 2011). Finally, in this context, our findings indicate that one should take into account the individual genetic makeup when evaluating treatment effects.

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Effects of a Common Variant in the CD38 Gene on Social Processing in an Oxytocin Challenge Study: Possible Links to Autism - Neuropsychopharmacology

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The intranasal application of oxytocin (OT) has been shown to influence behavioral and neural correlates of social processing. These effects are probably mediated by genetic variations within the OT system. One potential candidate could be the CD38 gene, which codes for a transmembrane protein engaged in OT secretion processes.

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https://www.nature.com/articles/s41576-021-00414-z

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Despite the difficulties in validating causative mutations and variants, genetic studies into both rare and common obesity over the past two decades have revealed two surprisingly cogent, overarching biological messages: first, the leptin-melanocortin pathway is a key appetitive control circuit (Fig. 4); and second, genes that are either enriched or exclusively expressed within the brain and CNS have a central role in obesity.

Pro-opiomelanocortin (POMC)-expressing neurons and agouti-related protein (AGRP)-expressing neurons within the arcuate nucleus of the hypothalamus (ARC) act to sense circulating leptin (LEP) levels, which reflect fat mass. These neurons signal to melanocortin 4 receptor (MC4R)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN), which controls appetite, thus linking long-term energy stores to feeding behaviour. Binding of class 3 semaphorins (SEMA3) to their receptors NRP and PLXNA influences the projection of POMC neurons to the PVN. Binding of brain-derived neurotrophic factor (BDNF) to its receptor neurotrophic receptor tyrosine kinase 2 (NTRK2) is thought to be an effector of leptin-mediated synaptic plasticity of neurons, including those in the ARC and PVN. The transcription factor SIM1 is crucial for the proper development of the PVN. +, agonist; −, antagonist; LEPR, leptin receptor; MRAP2, melanocortin receptor accessory protein 2; MSH, melanocyte-stimulating hormone; SH2B1, SH2B adaptor protein 1.

The leptin-melanocortin pathway and MC4R

Leptin is a key hormone secreted by adipocytes, which circulates at levels in proportion to fat mass. Leptin also responds to acute changes in energy state, as its levels decrease with food deprivation and are restored during re-feeding. Administration of leptin to fasted mice abrogates many of the neuroendocrine consequences of starvation, suggesting that the normal biological role of leptin is to initiate the starvation response. Leptin signals through the LEPR, which exists in several different isoforms. However, obesity-related effects of leptin are predominantly mediated by a long isoform that contains an intracellular domain (LEPRb), which is expressed in various regions of the CNS.

Within the arcuate nucleus (ARC) of the hypothalamus, LEPRb is found on two populations of neurons at the heart of the melanocortin pathway, one of which expresses POMC and the other agouti-related protein (AGRP) (Fig. 4). POMC is post-translationally processed by prohormone convertases to produce several biologically active moieties, including β-lipotrophin and β-endorphin, and, crucially, the melanocortin peptides adrenocorticotrophin (ACTH) and α-, β- and γ-melanocyte-stimulating hormone (MSH). The ARC POMC neurons project to MC4R neurons within the paraventricular nucleus (PVN) where melanocortin peptides signal to decrease food intake. By contrast, AGRP acts as an endogenous antagonist of MC4R to increase food intake. MC3R is another centrally expressed receptor that binds to both melanocortin peptides and AGRP; however, as mice with targeted deletions in the gene are not obese but instead have altered fat to lean mass ratio, MC3R is less likely to be related to food intake and more likely to be involved in nutrient partitioning.

We can state with confidence that the fine balance of melanocortinergic agonism and AGRP antagonism of MC4R, in response to peripheral nutritional cues such as leptin, plays a central part in influencing appetitive drive. The genetic evidence clearly supports this contention, with mutations in most genes of the melanocortin pathway resulting in hyperphagia and severe obesity in both humans and mice. In fact, the vast majority of single-gene disruptions causing severe early-onset obesity in humans fall within this pathway, including LEPR, POMC, AGRP, MCR4R, PCSK1 (ref.), SH2B1 (ref.), PHIP, MRAP2 (ref.) and SIM1 (ref.) (Fig. 4; Table 1). Mutations in MC4R in particular, are the most common single-gene defect leading to hyperphagia and obesity. Pathogenic mutations in MC4R are found in up to 5% of cases of severe childhood obesity and up to 0.3% of the general population. Of note, the degree of receptor dysfunction, as measured by in vitro assays, can predict the amount of food eaten at a test meal by an individual harbouring that particular mutation. Thus MC4R does not act in a binary on/off manner, but as a rheostat; put simply, the melanocortin pathway is a 'tunable' system. In addition to regulating food intake, it also regulates food preference, with individuals who carry mutations in MC4R showing a preference for food with higher fat content.

The importance of the melanocortin pathway in regulating feeding behaviour is highlighted by the identification of naturally occurring mutations in pathway genes in a wide range of different species where the appropriate selection pressure has been present (Table 1). For example, studies have found that 20-25% of Labrador retrievers, which are known to be more food-motivated than other dog breeds, carry a 14-bp deletion in POMC that disrupts the β-MSH and β-endorphin coding sequences and is associated with greater food motivation and increased body weight. Also, certain breeds of pig have been shown to carry MC4R missense mutations that are associated with fatness, growth and food intake traits. MC4R mutations even contribute to the adaptation and survival of blind Mexican cavefish to the nutrient-poor conditions of their ecosystem.

Other neuronal circuits and molecules linked to severe obesity

It is now clear that in addition to engaging classical neuropeptide-receptor systems within the brain, leptin also rapidly modifies synaptic connections between neurons, and that this structural plasticity is crucial to its downstream functions. One of the ways in which this plasticity is thought to be achieved is via brain-derived neurotrophic factor (BDNF) signalling to its receptor TrkB. BDNF is widely expressed in the CNS where it plays an important part in neuronal development. In the hippocampus, BDNF contributes to synaptic plasticity and long-term potentiation associated with memory and learning. However, evidence has emerged that implicates BDNF and TrkB in the regulation of mammalian eating behaviour and energy balance. BDNF is downregulated by nutritional deprivation and upregulated by leptin within the ventromedial nucleus (VMN) of the hypothalamus, although this regulation is probably indirect, as very few VMN BDNF neurons express the LEPR (Fig. 4) and some evidence indicates that it acts at least in part downstream of melanocortin signalling. Crucially, genetic disruption of BDNF and TrkB in both humans and mice results in hyperphagia and severe obesity.

Another group of neuronal proteins important in the development of neuronal circuitry and linked to energy balance are the class 3 semaphorins (SEMA3A-G). A study in humans found that 40 rare loss-of-function variants in SEMA3A-G and their receptors (PLXNA1-4, NRP1 and NRP2) were significantly enriched in 982 individuals with severe obesity compared with 4,449 controls. Disruption of several of these genes in zebrafish caused increased somatic growth and/or adiposity, and experiments with mouse hypothalamic explants suggest that SEMA3 signalling via NRP2 receptors drives the development of POMC projections from the ARC to the PVN. However, given that these results are from a single study, more data are required to confirm the exact role of class 3 semaphorins in energy homeostasis.

Insights from genetic loci linked to common obesity

Unlike candidate gene studies, GWAS make no a priori assumptions about the underlying biology that links genetic variants to a disease of interest. While this agnostic approach allows for new biological insights, the vast majority of GWAS-identified variants map to the non-coding parts of genes or to regions between genes. As such, they do not directly disrupt the protein-coding regions, but instead overlap with regulatory elements that influence expression of genes in close proximity or even over long distances.

However, even if the causative genes are unknown, pathway, tissue and functional enrichment analyses based on the genes located in the GWAS loci can provide insights into potential mechanisms. Since the very first GWAS for BMI, such analyses have pointed to the CNS being a key player in body-weight regulation, consistent with insights from human and animal models of extreme obesity. Recent analyses that include the latest BMI-associated loci, combined with updated multi-omics databases and advanced computational tools, have further refined these observations. In addition to the hypothalamus and pituitary gland (which are both known appetite regulation sites), other brain areas have been highlighted, including the hippocampus and the limbic system (which are involved in learning, cognition and emotion) and the insula and the substantia nigra (which are related to addiction and reward). The enrichment of immune-related cells (such as lymphocytes and B cells) and adipose tissue was found to be weaker.

Although enrichment analyses provide preliminary insights into the broad biology represented by genes in the GWAS loci, determining which genes, variants and/or underlying mechanisms are causal has proved an arduous task. For example, the FTO locus, which was identified more than a decade ago and harbours six genes, is the most extensively studied GWAS-identified obesity locus (Fig. 5). Despite its highly significant and widely replicated association with obesity, the causal variants and/or genes in the FTO locus have not yet been pinpointed with convincing evidence, and the mechanisms by which the locus affects body weight have not been fully elucidated. Early functional follow-up analyses suggested that FTO itself might be responsible, as Fto deficiency in mice results in a lean phenotype, whereas Fto overexpression is associated with increased body weight. Studies in mice have suggested that FTO plays a role in cellular nutrient sensing. Other studies found evidence that FTO influences brain regions that affect appetite, reward processing and incentive motivation by regulating ghrelin levels in humans or by controlling dopaminergic signalling in mice. In addition, variants in the FTO locus were shown to alter a regulatory element that controls the transcription of Rpgrip1l in mice, a ciliary gene located immediately upstream of Fto. Mice with reduced Rpgrip1l activity exhibit hyperphagic obesity, possibly mediated through diminished leptin signalling. In recent years, studies in human and animal models have shown that variants in the FTO locus directly interact with the promoter of Irx3, a gene located 0.5 Mb downstream of FTO. Irx3-deficient mice were found to exhibit weight loss and increased metabolic rate with browning of white adipose tissue, without changes in physical activity or appetite. Further in-depth functional characterization showed that rs1421085 in the FTO locus disrupts a conserved binding motif for the transcriptional repressor ARID5B, which leads to a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. The authors argue that increased expression of these genes results in a developmental shift from energy-dissipating beige adipocytes to energy-storing white adipocytes, a fivefold reduction in mitochondrial thermogenesis and increased lipid storage. However, given that multiple studies have shown that the FTO locus is robustly associated with food intake, with no evidence to date linking it to changes in energy expenditure, the relevance of this observation to the actual observed human phenotype still needs to be explored. A recent study reports that the FTO locus affects gene expression in multiple tissues, including adipose tissue and brain, and, more broadly, that the genetic architecture of disease-associated loci may involve extensive pleiotropy and allelic heterogeneity across tissues.

FTO contains nine exons (depicted by blue rectangles) and the body mass index (BMI)-associated SNP identified in genome-wide association studies (depicted by a red ×) maps to intron 1. IRX3 and RPGRIP1L have both been proposed to be the causal genes for obesity within the locus and to act on body weight through distinct mechanisms. HFD, high-fat diet.

Besides the FTO locus, functional follow-up analyses have been performed for only a few obesity-associated GWAS loci. For example, early studies identified a cluster of variants just downstream of TMEM18 (refs). TMEM18 encodes a poorly characterized transmembrane protein that is highly conserved across species and widely expressed across tissues, including in several regions of the brain. Tmem18 deficiency in mice results in a higher body weight owing to increased food intake, whereas Tmem18 overexpression reduces food intake and limits weight gain. A knockdown experiment in Drosophila melanogaster suggests that TMEM18 affects carbohydrate and lipid levels by disrupting insulin and glucagon signalling.

Two other GWAS loci for which functional analyses have been performed are located just upstream of CADM1 (ref.) and in CADM2 (ref.), genes that encode cell-adhesion proteins of the immunoglobulin superfamily and mediate synaptic assembly in the CNS. The BMI-increasing alleles at each locus are associated with increased expression of CADM1 and CADM2 in the hypothalamus. Deficiency of either Cadm1 or Cadm2 in mice results in a lower body weight and increased insulin sensitivity, glucose tolerance and energy expenditure without any change in food intake. Conversely, increased neuronal expression of either Cadm1 or Cadm2 is associated with elevated body weight. Furthermore, CADM1 is expressed in POMC neurons and Cadm1 deficiency leads to an increase in the number of excitatory synapses, suggestive of an increased synaptic plasticity. Cadm2-deficient mice exhibit increased locomotor activity and higher core body temperature.

Another GWAS locus, just upstream of NEGR1, harbours two deletions associated with increased obesity risk. These deletions do not overlap with the coding sequence of NEGR1, but encompass a conserved transcription factor-binding site for NKX6.1, a potent transcriptional repressor. Loss of binding of NKX6.1 leads to higher NEGR1 expression, which is consistent with the observation that BMI-increasing alleles (that is, deletions) at this locus are associated with higher NEGR1 expression in the brain. Similar to CADM1 and CADM2, NEGR1 is a cell-adhesion molecule of the immunoglobulin superfamily that is expressed in several regions of the brain and has been shown to have a role in brain connectivity, a process believed to be important in obesity. NEGR1 deficiency in mice was shown to result in lower body weight, mainly due to reduced lean mass, mediated by lower food intake. However, two other functional studies, one in mice and one in rats, found that knockdown of Negr1 expression resulted in the opposite phenotype - increased body weight and food intake. While NEGR1 deficiency in mice was found to impair core behaviours, so far, findings and proposed mechanisms are not fully aligned.

Taken together, functional follow-up analyses for these loci are slowly expanding our understanding of the pathophysiology that drives weight gain. However, many more obesity-associated loci are waiting to be translated into new biological insights. A major hurdle in translating GWAS loci into plausible candidate genes and appropriate paradigms for functional research is the annotation of the associated variants in a locus. Defining the regulatory function of the non-coding variants, identifying their putative effector transcripts and determining their tissues of action remains an ongoing challenge. The advent of high-throughput genome-scale technologies for mapping regulatory elements, combined with comprehensive multi-omics databases, advanced computational tools and the latest genetic engineering and molecular phenotyping approaches, is poised to speed up the translation of GWAS loci into meaningful biology.

Converging results from monogenic and polygenic forms of obesity

Gene discovery is often dichotomized by allele frequency and disease prevalence; that is, mutations are sought for monogenic forms of obesity and common variants for polygenic obesity (Fig. 2). However, it is increasingly recognized that monogenic and polygenic forms of obesity are not discrete entities. Instead, they lie on a spectrum and share - at least in part - the same biology. As GWAS have continued to discover more obesity-associated loci, an increasing number of these loci harbour genes that were first identified for extreme and early-onset obesity in humans or animal models, including MC4R, BDNF, SH2B1 (refs), POMC, LEP, LEPR, NPY, SIM1 (ref.), NTRK2 (ref.), PCSK1 (ref.) and KSR2 (ref.). In fact, most of these genes encode components of the leptin-melanocortin and BDNF-TrkB signalling pathways (Table 1). Thus, whereas genetic disruption of components of these pathways results in severe obesity, genetic variants in or near these same genes that have more subtle effects on their expression will influence where an individual might sit in the normal distribution of BMI.

Although most genes have been first identified for extreme forms of obesity, a locus harbouring ADCY3 was first identified in GWAS for common obesity, and ADCY3 was subsequently confirmed as having a role in extreme obesity. ADCY3 encodes an adenylate cyclase that catalyses the synthesis of cAMP, an important second messenger in signalling pathways. There is some evidence that ADCY3 (adenylate cyclase) colocalizes with MC4R at the primary cilia of PVN neurons and that cilia are required specifically on MC4R-expressing neurons for the control of energy homeostasis. In mice, disruption of Adcy3 or Mc4r in the cilia of these neurons impairs melanocortin signalling, resulting in hyperphagia and obesity.

As more GWAS loci are reported, we expect that findings across different lines of obesity research will continue to converge, providing accumulating evidence for new biology.

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The genetics of obesity: from discovery to biology - Nature Reviews Genetics

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The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people's health. Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarized as distinct diseases. However, gene discovery studies for both forms of obesity show that they have shared genetic and biological underpinnings, pointing to a key role for the brain in the control of body weight.

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NCD Risk Factor Collaboration (NCD-RisC): é uma rede de cientistas da saúde em todo o mundo que fornece dados rigorosos sobre fatores de risco para doenças.

Bardet–Biedl: é uma doença genética que se caracteriza por obesidade central, disfunção renal, polidactilia etc.

Prader–Willi: é uma doença genética rara que resulta em uma série de problemas físicos, mentais e comportamentais. Uma característica fundamental da síndrome de Prader-Willi é uma sensação constante de fome que geralmente começa por volta dos 2 anos de idade.

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CD38 associado ao desenvolvimento de melhores relações conjugais

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CD38 associado ao desenvolvimento de melhores relações conjugais

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https://www.nature.com/articles/s41598-021-82307-z

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Introduction

Satisfying romantic relationships play a critical role in helping people reach important goals, such as those relevant to career, social life, and health1,2,3,4,5. Perhaps most notably, several meta-analyses demonstrate that satisfying relationships are reliable predictors of better mental and physical health4,5, an effect that is at least as powerful as other notable predictors of health, such as physical activity and quitting smoking3. Although several mechanisms likely explain this association6, many appear to stem directly from high levels of relationship satisfaction7. But unfortunately, remaining satisfied in a long-term romantic relationship is notoriously difficult. Not only do divorce rates in numerous industrialized countries hover between 30 and 50%8,9, relationship satisfaction typically declines even in the relationships that remain intact [e.g.,10]. That said, there is substantial variability in the extent to which people remain satisfied over time [e.g.,11], with some people remaining quite satisfied. Given the implications of relationship satisfaction for health and well-being, understanding the factors that determine whether people remain satisfied, or become dissatisfied, may have important practical implications.

Critically, many challenges couples face over the course of their marriage are often present from the beginning, which is consistent with research suggesting that some marital difficulties stem from stable individual difference factors15,16. In the current research, we focused on one genetic source of individual differences-individual variation on the CD38 gene ( CD38), a gene that has been linked to social cognition and behavior in rodents17, and to positive outcomes in human romantic relationships18,19. Specifically, we sought to test whether CD38 is associated with cognitions and perceptions that help couples strengthen their pair-bond during the challenging newlywed period.

Considerable research, primarily with rodents, has revealed important insights into the biological processes underpinning the maintenance of pair-bonds. Beginning with seminal work on monogamous prairie voles, several decades of research have illuminated the importance of the oxytocin system in pair-bonding behavior in non-human animals23,24,25,26. Notably, recent research has built on this work to suggest a role of peripheral oxytocin levels, and exogenous administration of oxytocin, in attraction and pair-bonding processes in humans [27,28,29,30,31,32; c.f.33], as well as in more general processes relevant to social relationships such as trust34, perception of others' emotions, cooperative communication38, and coping with stress32.

In addition to suggesting that peripheral oxytocin levels and exogenous oxytocin administration play a role in human social behavior, research also suggests that genetic differences relating to the oxytocin system play a role in human social behavior. For example, variations in the oxytocin receptor gene ( OXTR), such as on the polymorphism rs53576, are linked to supportive communication with one's romantic partner39, and marital satisfaction in a sample of adults over 5040. Notwithstanding these two studies, recent meta-analyses disagree on whether rs53576 is linked to human sociality generally, with evidence for a link between OXTR variation and bonding within close relationships being particularly inconsistent43.

More recently, however, a different gene- CD38-has been implicated in the regulation of oxytocin release and social relationship processes. CD38 codes for the transmembrane glycoprotein CD38, which has numerous functions throughout the body. Preliminary evidence suggests that one such function is the modulation of oxytocin release17. Specifically, CD38 knockout mice (vs. wild-type mice) demonstrated lower plasma oxytocin levels, which, in turn, led to deficits in social cognition and in maternal behavior17. Consistent with the non-human animal work, recent studies in humans also support the link between CD38 and adaptive cognitive and behavioral interpersonal processes18,19,46,47. These studies have primarily focused on a single-nucleotide polymorphism (SNP), rs3796863, of either an adenine (A) or cytosine (C) located within an intron. For example, one study revealed that young adults with the CC genotype perceived more support from their peers than those with the AC/AA genotypes46. In another study, young adults with the CC genotype reported reduced feelings of alienation from their peers and lower rates of suicidal ideation than those with the AA genotype47.

More directly relevant to the present research, two studies have linked genetic variation in rs3796863 and pair-bonding processes in romantic relationships. One study demonstrated that, compared to those with the AC/AA genotypes, people with the CC genotype, who were in romantic relationships lasting at least 6 months, expressed more gratitude towards their partner, and had more positive responses to their partners' expressions of gratitude18. Gratitude appears to function, at least in part, to maintain intimacy and relationship satisfaction48, at least when it occurs in both members of a close relationship49, which suggests CD38 may ultimately facilitate bonding in humans. Indeed, another study demonstrated that this same CD38 SNP was associated with other relationship maintenance processes. Specifically, in a study using an intensive repeated measurement method to study couples' daily behavior, Sadikaj and colleagues19 showed that those with the CC (vs. AC/AA) genotype reported engaging in more communal behaviors (e.g., "I expressed affection with words or gestures") during their interactions with their partner. Furthermore, people with the CC genotype (vs. AC/AA genotypes) perceived their partner as more communal during these interactions, experienced less negative affect, felt less insecure, and reported better overall relationship adjustment. Taken together, these studies suggest that rs3796863 may play an important role in promoting pair bonding and intimacy through a variety of relationship maintenance processes.

Nevertheless, it remains unclear whether the link between rs3796863 and specific relationship bonding processes (e.g., gratitude, communal behavior) translates into higher levels of global relationship satisfaction that are independent of those processes themselves, as well as what other relationship maintenance processes may be involved. We leveraged data from a longitudinal study of newlywed couples to examine these issues. Specifically, 71 newlyweds ( N = 142 people) completed a battery of questionnaires regarding their relationship cognitions, bonding-related problems, non-bonding-related problems, and relationship satisfaction at a baseline assessment (within 3 months of their wedding); both spouses then reported on their marital satisfaction every four months for the next 3 years (see " Methods"). Participants also provided saliva samples from which we obtained DNA (139 individuals were successfully genotyped). Given the aforementioned research, we focused on variation in rs3796863. It is worth mentioning that Algoe and Way18 also examined another CD38 SNP, rs6449182, which demonstrated stronger links to gratitude measures; however, we chose to focus on rs3796863 because it has been the focus of the majority of studies on human close relationships, and, moreover, one study identified limited variability on rs644918219.

In our data analytic strategy, we sought to conceptually replicate and extend the findings linking the CC genotype to gratitude17. We predicted that individuals with the CC (vs. AC or AA) genotype would report higher levels of gratitude toward their spouse. Further, given evidence that people with the CC genotype demonstrate other processes that serve to promote bonding, we investigated the association between rs3796863 and forgiveness50, a related but independent relationship maintenance process, as well as trust, a critical downstream implication of such processes51. We predicted that CC individuals would report higher trust in their partner, and would be more forgiving of their partner, than their AC or AA counterparts. We also sought to conceptually replicate and extend prior work linking rs3796863 to global relationship adjustment18; in line with that research, we predicted that CC individuals would report greater marital satisfaction than their AA/AC counterparts. Here, we also tested whether rs3796863 is associated with discrete processes that should contribute to relationship satisfaction-namely, perceptions of problems in domains related to pair-bonding and intimacy (e.g., showing affection, amount of time spent together, sex, trust, communication). We predicted that CC (vs. AC or AA) individuals would report fewer pair-bonding problems, but not, importantly, fewer problems in other domains (e.g., friends, religion, money management, decision-making). Finally, we investigated whether the variation in rs3796863 predicted longer-term relationship outcomes by examining the trajectories in relationship satisfaction over the first 3 years of marriage. As noted, this is a particularly vulnerable time for couples; as such, this is a rigorous test of the role of CD38 in relationship maintenance.

Of note, in order to make the best use of this data set, we also conducted a number of exploratory analyses to test associations between rs3796863 and other processes relevant to pair-bonding that were included in the questionnaires that newlywed couples completed at the start of marriage, including attachment insecurity, commitment, perceptions of romantic alternatives, and jealousy. Although we had did not have strong a priori predictions, these exploratory analyses are valuable in at least two ways. First, they provide insight into potential novel associations between rs3796863 and relationship processes not examined in prior studies. Second, even non-significant associations involving these variables may offer insight into the ways that rs3796863 is discriminately associated with relationship functioning.

Results

We tested our hypotheses using multilevel modeling, which accounts for the non-independence of responses from husbands and wives (see " Methods" for a comprehensive description of our data analytic approach). Some research suggests racial differences in the prevalence of the reference allele contributing to the CC genotype, such that African Americans have a reference allele frequency of 0.3764 compared to approximately 0.7 for individuals of European ancestry52,53. Although we did not have access to our participants' ancestry, participants did self-report racial information. To ensure that any effects we observed were not due to racial differences in CC prevalence rates, we conducted supplemental analyses to examine the moderating role of race/ethnicity, which are reported in the main text, as well as exploratory analyses to examine race differences on any of the dependent variables, which are described in see Supplemental Materials. We thank an anonymous reviewer for this suggestion.

Effects of rs3796863 on gratitude, trust, forgiveness, martial satisfaction & perceptions of marital problems at the start of marriage

We first examined the associations between rs3796863 and aspects of marital functioning that we predicted based on the prior literature. Results are presented in Table 1. All associations remained significant when controlling for multiple comparisons54, and none of these associations were moderated by sex. As can be seen, the data provided strong support for the hypothesis that the rs3796863 CC genotype is associated with bonding-relevant relationship cognitions in newlywed couples. Specifically, as predicted, CC individuals felt more grateful for their partner, reported higher trust in their partner, were more forgiving of their partner, and were more satisfied with their marriages than were AC/AA individuals. All these effects remained significant in analyses that controlled for self-identified race (see Supplemental Materials), and race did not moderate the association between rs3796863 and gratitude ( p = 0.598), trust ( p = 0.187), forgiveness ( p = 0.778), or marital satisfaction ( p  = 0.117). Although rs3796863 was also associated with perceptions of marital problems in domains relevant to pair-bonding and intimacy (e.g., affection, communication), this association was moderated by race, such that rs3796863 was associated with higher problems among Black participants but not among non-Black participants. Given that we only had 18 participants self-identify as Black, and given that the interaction effect fell just below the threshold for statistical significance, we are hesitant to draw strong conclusions about this effect, especially given that other factors correlated with race may explain it.

Table 1 Primary analyses: associations between CD38 rs3796863 and bonding-relevant cognitions.

In sum, as predicted, variation in CD38 rs3796863 was associated with gratitude, trust, forgiveness, and relationship satisfaction. These data thus provided strong support for the hypothesis that the rs3796863 CC genotype is associated with bonding-relevant relationship cognitions in newlywed couples.

Do relationship maintenance processes mediate the effects of rs3796863 on satisfaction?

Next, we examined whether the association that emerged between rs3796863 and marital satisfaction did so through its effects on the specific relationship maintenance processes. That is, we tested whether people with the CC genotype were more satisfied with their marriages than those with the AC/AA genotype because they are more grateful for, trusting of, and/or forgiving of their partner. To this end, we used the RMediation package55,56 to test for these indirect effects. These tests of mediation compute indirect effects based on the coefficients and standard errors of path a and path b. Path a is the association between the predictor and each purported mediator. The coefficients and standard errors for these are reported in the top three rows of Table 1. Path b captures the association between each mediator and marital satisfaction. The coefficients and standard errors for these were estimated in a single new multilevel model that regressed marital satisfaction onto gratitude, trust, and forgiveness simultaneously, while controlling rs3796863 (see Fig. 1). According to these analyses, only trust mediated the effects of rs3796863 on marital satisfaction, b = − 0.21, SE = 0.09, p < 0.05, 95% CI [− 0.39, − 0.05]; controlling trust, the indirect effects of both gratitude, b = − 0.005, SE = 0.04, 95% CI [− 0.08, 0.07] and forgiveness, b = − 0.04, SE  = 0.04, 95% CI [− 0.14, 0.02], did not reach significance as evidenced by confidence intervals that overlap with 0. These analyses indicate that participants with the CC genotype (compared to those with the AC/AA genotypes) felt more trust toward their partner, which led them to feel more satisfied in their marriages.

Path b coefficients from the mediation model are shown. Marital satisfaction, gratitude, trust, and forgiveness were standardized. Path a coefficients for the associations between rs3796863 and gratitude, trust, and forgiveness are reported in Table 1. Trust significantly mediated the association between rs3796863 and marital satisfaction. * p < 0.05 *** p  < 0.001.

Exploratory analyses on change in marital satisfaction

Next, we examined whether the CC individuals remained more satisfied than AC/AA individuals over time by estimating a multilevel growth curve model that included separate fixed and random intercept and time effects for husbands and wives (see Fig. 2). Rs3796863 was not associated with change in relationship satisfaction over time, b = − 0.01, SE = 0.02, t(64) = − 0.72, p = 0.473. However, re-centering the time variable such that the intercept represented the end of the study revealed that CC individuals were more satisfied than AC/AA individuals at the end of the study, although this association did not quite reach significance, b = − 0.35, SE = 0.19, t(64) = − 1.86, p  = 0.068, perhaps due to increased error variance, due to attrition and other factors. In other words, initial differences in marital satisfaction appeared to remain mostly stable over time.

Associations between CD38 rs3796863 and marital satisfaction over the first 3 years of marriage.

Exploratory analyses at start of marriage

Several notable findings also emerged in our exploratory analyses (see Table 2). First, compared to AC/AA individuals, CC individuals reported higher levels of commitment. Second, compared to husbands with the AC/AA genotypes, husbands with the CC genotype reported a stronger sense of couple identity and were less likely to notice romantic alternatives during the 14-day daily diary portion of the study. These associations were significantly different from the non-significant effects that emerged among wives. There was no association between rs3796863 and jealousy or attachment insecurity, or several other processes that have been shown to promote relationship functioning. Consequently, although these analyses are exploratory they buttress the hypothesis that rs3796863 may be associated with specific aspects of relationship maintenance rather than general positivity.

Table 2 Exploratory analyses: Associations between CD38 rs3796863 and relationship processes.

Notably, given the fact that our data also offered insights into potential associations between each gene and partner processes and outcomes, we again tested effects of partner CD38 on all variables, but no partner effects reached significance (not reported).

Discussion

We capitalized on data from a longitudinal study of newlywed couples to examine whether variation on the CD38 SNP rs3796863 was associated with relationship processes and outcomes in newlywed couples. Consistent with our predictions, among both men and women, the CC (vs. AC/AA) genotype was associated with reporting more gratitude toward one's partner, trust in one's partner, and forgiveness of one's partner. Moreover, participants with the CC genotype (vs. AC/AA) reported higher levels of relationship satisfaction, an observation that also replicates prior research19. Interestingly, additional analyses revealed that the association between rs3796863 and marital satisfaction was mediated by trust-that is, the reason why those with the CC genotype were more satisfied is because they were more trusting of their partner. This finding is consistent with work suggesting that trust is a key process underlying and explaining the significance of more distal dispositional and cognitive processes that influence romantic relationship dynamics51. The trust findings is consistent with prior work linking intranasal oxytocin administration with increased trust34, at least among those who were less trusting at baseline57. Finally, there was suggestive evidence that CC (vs. AC/AA) continued to be more satisfied after 3-years or marriage, suggesting that the effects of rs3796863 may endure over time, although the fact that this effect did not reach traditional levels of significance indicates it should be treated with caution until replicated.

Our finding that CD38 is associated with gratitude conceptually replicates and extends findings from several prior studies of romantic couples18,19. For example, consistent with Algoe and Way18, we found that CC individuals were more likely than AC/AA individuals to report feeling and expressing gratitude toward their partner. Similarly, consistent with Sadikaj and colleagues19, we found that CC individuals reported higher levels of marital satisfaction. Importantly, however, our research extends this prior work. First, we show that the effects of the CD38 SNP extend to other bonding-relevant relationship cognitions (i.e., trust and forgiveness), and we show that it is trust, in fact, that mediates the effect of rs379686 on marital satisfaction. In fact, perhaps the most novel aspect of our work was linking all these processes together, showing that it was specifically the greater levels of trust experienced by those with CC genotype that helped explain why such individuals were more satisfied with their marriages.

Future research may benefit from examining other pathways that may explain the link between the AC/AA genotype and lower relationship satisfaction. Recent research suggests that people with the AC/AA genotype (compared to those with the CC genotype) have increased social sensitivity58,59. Specifically, adolescents with the AC/AA genotypes (i.e., carriers of the A allele) tracked over the course of 6 years demonstrated higher social anxiety and depression-if they faced high levels of interpersonal stress58. Although romantic relationships are associated with numerous psychological and physiological benefits1,2,3,4,5, they are also inherently stressful because even the happiest of couples inevitably have problems60. Research suggests that when faced with relationship conflict people engage in risk-regulation to manage the competing goals of self-protection and relationship promotion60. In such conflict situations, it may be that AC/AA individuals are more likely than CC individuals to shift toward self-protection, thereby lowering their dependence on and intimacy with their partner. In fact, recent research has linked the AC/AA genotype to neuroticism59; although this research focused on the link between neuroticism and social anxiety, neuroticism is also reliably linked to lower relationship satisfaction61. Consequently, future research may benefit from examining whether variation on rs3796863 mediates the link between neuroticism and marital satisfaction.

Although our understanding of the functional significance of the rs3796863 SNP in humans remains incomplete, research in rodent models indicates that CD38 influences the synthesis and secretion of oxytocin17. Our finding that rs3796863 predicted relationship satisfaction over the course of the newlywed period resonates with other work showing that peripheral oxytocin levels were associated with relationship survival during the perinatal transition period32, and facilitated relationship survival in dating couples31. We have more to learn about the precise mechanisms by which this polymorphism influences relationship processes. Rs3796863 is located within an intron of the CD38 gene, meaning that these changes occur in the non-coding region of DNA. They could contribute to regulating the expression of these genes, or simply serve as markers that are closely linked to nearby genetic variants of functional significance. Future work is needed to better understand not only the functional significance of this polymorphism in humans but also the pathway(s) by which it influences relationship maintenance processes.

In contrast to all of our primary hypotheses, which held when correcting for multiple tests, our exploratory analyses involved numerous statistical tests, which can increase the chance of spurious effects. Accordingly, readers should be cautious in interpreting those effects. That said, several of the significant effects that emerged in our exploratory analyses were consistent with the overall pattern of predicted effects. For example, participants with the CC (vs. AC/AA) genotype were more committed to the relationship. Commitment is thought to be, at least partly, a downstream consequence of marital satisfaction; thus the effects of the CC genotype on commitment may come about because of its effects on marital satisfaction and/or other more proximal bonding-related processes (e.g., trust). Interestingly, our exploratory analyses also identified two effects specific to men: husbands with the CC genotype (vs. husbands with the AC/AA genotypes) tended to report having a stronger couple identity and were less interested in romantic alternatives. Couple identity is a facet of commitment that is associated with greater personal dedication to the relationship, specifically the perception that one and one's partner are a team62. Attractive alternatives, on the other hand, are a threat to relationship commitment; paying less attention to and devaluing alternatives is associated with better relationship outcomes and pair-bond maintenance63. Although most other effects of rs3796863 were consistent across husbands and wives, these latter findings suggest that rs3796863 may affect men's commitment through these additional routes. Overall, findings from the primary and exploratory analyses are consistent with the idea that the CC genotype predisposes people to evaluate their relationships more positively and engage in benevolent cognitions that promote intimacy. Notably, people's attachment anxiety and attachment avoidance were not associated with rs3796863. This may be because attachment is strongly influenced by social learning and caregiver behavior64 rather than genetic predispositions; other genetic polymorphisms in the oxytocin system (such as variation on the SNP rs53576 of the oxytocin receptor gene) are similarly not linked to attachment insecurity65. Nevertheless, future research may benefit from conceptually replicating the specific effects in both our primary and exploratory analyses.

Several limitations of this work are worth considering. First, our results are limited to a sample of individuals of European ancestry practicing Western cultural norms of romantic relationships. Not only are genetic differences differentially distributed in various ancestries, as noted, but the same genetic differences may be uniquely associated with romantic relationship processes in Western cultures compared to romantic relationships common to other cultures [e.g., arranged marriages66]. Future research may benefit from examining how genetic variation on CD38 may be associated with relationship processes in cross-cultural, more diverse, and larger samples. Additionally, the CC genotype may be differentially associated with relationship processes even within the North American culture. In our sample, Black participants reported more pair-bond related problems and lower marital satisfaction than non-Black participants (see Supplemental Materials). One reason for this association may be due to the fact that members of minority groups face greater sociodemographic stress and are more likely to have lower socioeconomic status (SES) coupled with the fact that SES is an important moderator for the effectiveness of relationship maintenance strategies67. It may be that the CC genotype exerts more powerful effects in these more vulnerable groups. The lack of diversity in our sample and the absence of targeted measures precluded us from examining these associations directly in the present data. Future research could examine whether factors such as race, socioeconomic status, and sociodemographic stress affect the link between variation on rs3796863 and perceptions of problems and/or relationship intimacy.

A second limitation is that, because our hypotheses were guided by prior work focusing specifically on rs3796863, we focused on this single polymorphism. Thus, our findings join a growing body of literature suggesting the involvement of CD38 in relationship processes, but do not preclude the role of other CD38 polymorphisms, or other genes, in relationship processes. Indeed, other polymorphic sites on CD38 (e.g., rs6449182) have been linked to relationship dynamics. Relatedly, it is important to acknowledge that there are legitimate concerns regarding the potential for spurious findings in candidate gene studies like this one, including potential issues with spurious findings and the oversimplification of-or even error regarding-the link between a gene and social behavior. Thus, although we had a priori hypotheses about the associations between rs3796863 and the marital processes we assessed, these hypotheses were based in a literature that may suffer from publication bias. To increase transparency of the present research, we have been explicit about the method, predictions, and results of all analyses conducted, and followed STREGA recommendations68. To our knowledge, there has not been a genome wide association study (GWAS) on romantic relationship maintenance as a quantitative trait in the GWAS catalog [ https://www.ebi.ac.uk/gwas/home; 69]. The present research will thus provide valuable phenotypic descriptions for future GWAS on romantic relationship maintenance. Given the associations reported in this paper, and in the prior literature, it would be important to conduct a GWA study examining marital satisfaction, bonding-relevant cognitions (e.g., trust, gratitude, forgiveness), and relationship changes over time.

A final limitation is our small sample size, which was dictated by our original longitudinal study of newlywed couples (a population that is notoriously difficult to recruit). We utilized all physiological samples that were available at the time when funding for the current research question was obtained, leaving us with data from 139 genotyped individuals for our analyses. Because we used a convenience sample to test the current predictions, our findings should be replicated. That said, our genotyped sample was comparable to or larger than those used in past research18,19. Overall, we hope these findings encourage more close relationships researchers to collect physiological samples so that data from several longitudinal samples can be pooled together to test future hypotheses.

Conclusion

Taken together, these findings offer new insights into research at the intersection of genetics and romantic relationships. Regarding relationships, these findings offer novel insights into important precursors that may help or hinder newlyweds as they navigate the first few years of marriage. Polymorphisms on the CD38 gene were associated with bonding-relevant cognitions (gratitude, trust, and forgiveness), and overall marital satisfaction over the course of the first 3 years of marriage. The reported results represent group-level effects that are relatively small in size and are just one potential source of variance in people's relationship processes and satisfaction over time. Regarding genetics, these findings support existing findings linking CD38 and the SNP rs3796863 to romantic relationship processes. Indeed, with the addition of our replication study to the existing literature18,19, there are now three independent samples, by three different research teams, that provide consistent evidence linking the CC genotype (compared to the AC/AA genotypes) to positive romantic relationship cognitions and outcomes.

Method

Participants

Participants were 142 people (from 71 couples). This sample was a subset of a larger, longitudinal study on newlywed relationships for whom samples for DNA analyses were collected. The larger sample contained a total of 240 members of 120 couples and has been described in prior research [e.g., 63]. Saliva samples from the other couples were either depleted prior to the funding that allowed the genetic assays or DNA could not be isolated. Additionally, given that some hypotheses were derived from perspectives of processes guiding heterosexual relationships, data were excluded from one couple in the sample that was not heterosexual. Husbands were on average 32 years old ( M = 32.20, SD = 10.98, range 20-72); wives were on average 30 years old ( M = 30.33, SD  = 8.48, range 21-55). For the majority of the couples this was their first marriage (76.1%) and most did not have children (73.9%). The majority of couples were White/Caucasian (73.2%). The study procedures were approved by the Florida State University Institutional Review Board (IRB) and research was conducted in accordance with the relevant guidelines and regulations set forth in the Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1979 as well as the American Psychological Association. All participants provided written informed consent to participate in the study.

Procedure

After telephone-based eligibility screenings, couples were sent either paper packets of questionnaires or an online, individualized link to a Qualtrics survey. Husbands and wives were instructed to complete the questionnaires independently prior to an upcoming lab session, which was scheduled within three months of their wedding. During the lab session, couples engaged in a series of problem-solving discussions and provided saliva samples via passive drool from which DNA was isolated. After the lab session, both couple members completed a brief survey every night for the 14 nights subsequent to the session (i.e., a daily diary). Finally, couple members responded to several of the same questionnaires again every four months for 3 years, including the measures of relationship satisfaction, which we analyzed in exploratory analyses.

Materials

Primary dependent measures

Gratitude

Participants reported their general disposition of gratitude toward their partner49,70. Participants rated the frequency with which they generally felt and expressed gratitude toward their partner (α = 0.82, e.g., I feel appreciation for the things that my partner does for me" on a scale of 1 (Never) to 5 (Frequently). Most participants expressed gratitude frequently ( M = 4.78, SD  = 0.34). We predicted that individuals with the CC genotype would report greater gratitude compared to individuals with the AC/AA genotypes.

Trust

Participants completed the Trust subscale of the Perceived Relationship Quality Components Inventory71 which included three questions (α = 0.86) about their trust toward their partner (e.g., "How much do you trust your partner?"). Participants responded using a 1 (Not at all) to 7 (Completely) scale. Most participants reported high levels of trust ( M = 6.56, SD  = 0.74). We predicted that individuals with the CC genotype would report greater trust compared to individuals with the AC/AA genotypes.

Forgiveness

Participants' forgiveness was measured by assessing their likelihood to forgive their partner if he or she committed five hypothetical marital transgressions that varied in severity [e.g., the partner snapped at and insulted the spouse; see72]. Participants reported whether they would express forgiveness for each scenario on a scale of 1 (Definitely no) to 7 (Definitely yes). Participants rated themselves to be slightly above the scale midpoint on average ( M = 4.76, SD  = 1.23). We predicted that individuals with the CC genotype would show a greater tendency to forgive their partners compared to individuals with the AC/AA genotypes.

Perceived severity of problems

Participants also completed the Inventory of Marital Problems73. The questionnaire asks participants to indicate on a scale of 1 (Not a Problem) to 11 (Major Problem) the extent to which each of the 19 different common marital problems is an issue for their marriage. Before conducting analyses, the first two authors independently separated the domains into three composites for the primary analyses and reconciled discrepancies. One composite comprised problems relevant to pair-bonding specifically (showing affection, amount of time spent together, recreation and leisure time, sex, trust, jealousy, and communication). The second comprised problems relevant to social interactions outside of the pair-bond (children; in-laws, parents, and relatives; friends). The third comprised problems in non-social areas of the relationship (religion, household management, making decisions, unrealistic expectations, independence, money management, solving problems, drugs and alcohol, career decisions). Participants did not perceive many problems in pair-bonding ( M = 2.65, SD = 1.43), in social interactions outside of the pair-bond ( M = 2.62, SD = 1.46), or in non-social domains ( M = 2.53, SD  = 1.45). We predicted that individuals with the CC genotype would report fewer problems relevant to pair-bonding (the first composite) compared to individuals with the AC/AA genotypes; the other domains of problems were included in the exploratory analyses because we had no strong predictions that they would differ based on rs3796863 genotype.

Marital satisfaction

Every four months for 3 years, participants completed three measures of relationship satisfaction: the Quality of Marriage Index74, the Semantic Differential75, and the Kansas Marriage Satisfaction scale76. Given all scales are meant to measure the same construct, global marital satisfaction, which is confirmed by the high correlations among the scales (all r's > 0.887), we standardized each scale by creating a Z-score and created a composite of the three measures (which was also standardized). As would be expected and as is reported elsewhere63, most newlyweds report being very satisfied with their marriages. We predicted that individuals with the CC genotype would report being more satisfied at the start of marriage compared to individuals with the AC/AA genotypes. We additionally explored whether the trajectory of marital satisfaction over the first 3 years of marriage was associated with variation on rs3796863.

Exploratory dependent measures

Because the broader study aim was to explore associations between rs3796863 and pair-bonding, the most relevant questionnaires to pair-bond strength and maintenance were chosen from the broader baseline battery. Before conducting analyses, the first two authors independently compiled lists of measures that were then reconciled into a complete list that is presented in this manuscript. No other questionnaires from the battery were examined in relation to rs3796863.

Commitment

Participants completed multiple commitment measures. Participants completed the Rusbult commitment scale77, which examined general desires toward commitment in their relationship (α = 0.72, M = 8.13, SD = 0.77, e.g., "I am committed to maintaining my relationship with my partner"). Participants also completed the Commitment Inventory62 which consisted of 10 subscales. We selected six subscales that were most relevant to pair-bonding: relationship agenda (α = 0.71, M = 6.71, SD = 0.56, e.g., "I want this relationship to stay strong no matter what rough times we may encounter"), couple identity (α = 0.76, M = 6.14, SD = 0.80, e.g., "I like to think of my partner and me more in terms of 'us' and 'we' than 'me' and 'him/her'"), prioritization of relationship (α = 0.75, M = 6.27, SD = 0.73, e.g., "My relationship with my partner comes before my relationships with my friends"), satisfaction with sacrifice (α = 0.84, M = 5.71, SD = 0.97, e.g., "It can be personally fulfilling to give up something for my partner"), availability of partners (α = 0.80, M = 3.64, SD = 1.19, e.g., "It would be very difficult for me to find a new partner"), and alternative monitoring (α = 0.73, M = 5.96, SD  = 1.02, e.g., "I am not seriously attracted to members of the opposite sex other than my partner"). We omitted the remaining four subscales because they did not seem to pertain to the pair-bond itself but instead captured broader individual differences and contextual variables: social pressure, perceived morality of divorce, structural investments, and meta-commitment. We created a composite (α = 0.74) of the two subscales relevant to alternatives but analyzed the other subscales individually.

Jealousy

Participants completed the Multidimensional Jealousy Scale78 which consists of three subscales that assess emotional, cognitive, and behavioral jealousy. For the emotional jealousy subscale, participants were asked to indicate how they would react emotionally to the situations described by each statement ( n = 8, α = 0.87, M = 4.50, SD = 0.99, e.g., "Your spouse comments to you on how great looking a particular member of the opposite sex is") on a scale of 1 (Very pleased) to 7 (Very upset). For the cognitive jealousy subscale, participants were asked to indicate how often they had thoughts about their partner described by each statement ( n = 7, α = 0.87, M = 1.70, SD = 0.88, e.g., "I suspect that my spouse is secretly seeing someone of the opposite sex") on a scale of 1 (Never) to 7 (All the time). For the behavioral jealousy subscale, participants were asked to indicate how often they engaged in behaviors described by each statement ( n = 8, α = 0.82, M = 1.85, SD  = 0.88, e.g., "I look through my spouse's drawers, handbag, pockets, phone, or emails") on a scale of 1 (Never) to 7 (All the time).

Noticing alternatives on a daily basis

Following the lab session, participants completed a two-week diary. Each day, participants answered a question "To what extent did you notice members of the opposite sex today?" on a scale of 1 (Not at all) to 7 (Very much). We averaged participants' answers across the diary days they completed ( M = 2.08, SD  = 1.36).

Attachment Insecurity

Participants reported their levels of attachment insecurity using the Experiences in Close Relationships Scale-Revised [ECR-R79]. The ECR-R is comprised of an attachment anxiety subscale (α = 0.92, M = 2.22, SD = 0.99, e.g., "I am afraid to lose my partner's love") and an attachment avoidance substance (α = 0.93, M = 2.23, SD  = 0.92, e.g., "I prefer not to show a partner how I feel deep down"). Participants rated their agreement with 18 statements per subscale on a 1 (Strongly Disagree) to 7 (Strongly Agree) scale.

Sexual satisfaction

Participants completed the Index of Sexual Satisfaction80, which contains 25 items (α = 0.93, e.g., "I think that our sex is wonderful") using a scale from 1 (None of the time) to 7 (All of the time).

Sexual frequency

We assessed sexual frequency in two ways. In the main questionnaire battery, participants responded to an open-ended question "Approximately how many times have you had sexual intercourse with your spouse over the past 4 months?" Additionally, in the two week diary that followed the initial lab session, participants reported daily whether they had sex with their partner. For analyses using the diary measure, we computed the percentage of each individuals' diaries completed during which sex was reported within the total number of diaries completed ( M = 29.91, SD  = 20.23).

Attributions

Participants completed the Relationship Attribution Measure81 that assesses people's attributions of negative behaviors from one's partner (e.g., one's partner criticizing the person). Participants responded using a scale from 1 (Not at all) to 7 (Completely) and we averaged responses across scenarios and attributions ( M = 3.66, SD  = 1.02).

Oppositional behavior

During the laboratory session that occurred within three months of the couples' wedding, couples engaged in a series of problem-solving discussions that were video recorded. Each individual's speaking turn was coded for oppositional behavior following an established coding scheme82. Oppositional behavior codes comprised 3 direct oppositional behaviors (blaming, rejecting, making demands of the partner) and 5 indirect oppositional behaviors (sarcasm, hostile joking, hostile questioning, mind-reading, denying responsibility). A second coder overlapped on 18% of the conversations (ICC = 0.74). Analyses focused on the proportion of actors' total speaking turns that received oppositional codes that were averaged across the four conversations ( M = 0.08, SD  = 0.10).

Automatic partner attitudes

During the lab session, participants completed the Partner Evaluative Priming Task that assessed automatic partner attitudes [for task description, see83]. Higher values represented more positive automatic partner attitudes ( M = 53.43, SD  = 103.29).

Automatic attention to romantic alternatives

During the lab session, participants completed a dot probe attention task that assessed the latencies with which they shifted their attention away from a quadrant on the computer screen in which target faces appeared to categorize a circle or a square in a different quadrant84. We examined latencies following the attractive opposite-sex targets ( M = 506.79, SD = 82.73) while controlling latencies following attractive same-sex targets, average same-sex targets, and average opposite-sex targets63.

Genotyping

Saliva samples were collected via passive drool into 20 mL plastic scintillation vials and frozen at − 20 °C immediately after the lab session. At a later time, samples were thawed and centrifuged. After we removed supernatant from each sample for the purpose of conducting hormone assays (not a focus of the current report), we froze the pellets again. Pellets were later thawed for a second time before purification. For most samples, pellets and some supernatant were pooled from two samples. We purified DNA using a protocol adapted from past research85. Out of 142 samples that we attempted to purify, we obtained adequate DNA concentrations from 139. We performed control analyses on agarose gel on 6 samples to test for DNA degradation; no issues with DNA integrity were observed. We used a Nanodrop to determine yield (average yield was 494 ng/μL) and 260/280 ratio. If the 260/280 ratio was below 1.80, samples were additionally run through a spin column from a Qiagen DNeasy Blood and Tissue kit following manufacturer instructions. DNA was diluted to 28 ng/mL in TE buffer before the assays.

Genotyping for single nucleotide polymorphisms was conducted using a Taqman SNP Genotyping Assay [rs3796863: C___1216944_10; which reports the nucleotides from the complementary (−) strand of the CD38 gene]. All samples were run in duplicates on the plate with complete concordance. Allele frequency did not differ based on participant sex, χ ²(2) = 0.841, p = 0.66. We followed previous work18,19 to code the CC genotype as 0 and AC/AA genotypes both as 1; genotype frequencies are reported in Table 3.

Table 3 Genotype counts for rs3796863.

Analytic strategy

We modeled the associations between relationship processes and genetic differences using multilevel modeling using the MIXED procedure in SPSS to control for the non-independent nature of couple data. For analyses examining measures assessed at baseline, we first estimated a model that tested for a moderation by sex for each gene. If the interaction was significant, we report the simple effects for both men and women. If the interaction was not significant, we removed the interaction term from the model, as well as participant sex if it was not significantly associated with the dependent variable, and report the main effect. For all effects, we report effect size r (equation below) which is comparable to a correlation coefficient [see86].

$$r=\sqrt{\frac{{t}^{2}}{{t}^{2}+df}.}$$

For the analyses examining the trajectory of satisfaction over 3 years, we estimated growth curves in HLM7 by regressing marital satisfaction onto separate intercepts and slopes for husbands and wives in Level 1 and then entering each gene at Level 2 to account for individual differences in the intercept term, which estimated beginning marital satisfaction, and slope terms, which estimated changes in marital satisfaction. We also estimated a second model in which the time variable was recentered such that the intercept represented marital satisfaction at the end of the study (3 years after baseline).

Data availability

These data cannot be deposited in a repository because participants did not consent to have their data made publicly available and because couple member data may be identifiable to each other. We will, however, make the data available upon request for such purposes as confirming study results, conducting meta-analyses, etc. A Data Access Committee, consisting of Drs. Makhanova and McNulty will assess requests for access to the data. Inquiries should be sent to Dr. McNulty at: mcnulty@psy.fsu.edu.

Acknowledgements

This material is based upon work supported by the National Science Foundation under Grant No. BCS-1251520 (to J.K.M) as well as funding provided by the Florida State University Council on Research and Creativity.

Author information

Affiliations

1. Department of Psychological Science, University of Arkansas, 216 Memorial Hall, Fayetteville, AR, 72701, USA

Anastasia Makhanova

2. Department of Psychology, Florida State University, 1107 W. Call St, Tallahassee, FL, 32306, USA

James K. McNulty, Lisa A. Eckel, Larissa Nikonova & Elizabeth A. D. Hammock

3. Department of Psychology, McGill University, 2001 McGill College Ave, Montreal, QC, H3A 1G1, Canada

Jennifer A. Bartz

Contributions

J.K.M. developed the study concept and study design for the longitudinal study; A.M. and J.K.M. developed the hypotheses for the research reported in this manuscript with input from J.A.B. and E.A.D.H. A.M. and L.N. conducted genotyping and assays, with input from L.A.E. and E.A.D.H. A.M. drafted the manuscript; J.K.M., L.N., L.A.E., J.A.B., and E.A.D.H. provided critical revisions. All authors approved the final version of the manuscript for submission.

Corresponding author

Correspondence to Anastasia Makhanova.

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The authors declare no competing interests.

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Makhanova, A., McNulty, J.K., Eckel, L.A. et al. CD38 is associated with bonding-relevant cognitions and relationship satisfaction over the first 3 years of marriage. Sci Rep 11, 2965 (2021). https://doi.org/10.1038/s41598-021-82307-z
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# data[].attributes.attachment_link.title
CD38 is associated with bonding-relevant cognitions and relationship satisfaction over the first 3 years of marriage - Scientific Reports

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Although there are numerous benefits to having a satisfying romantic relationship, maintaining high levels of relationship satisfaction is difficult. Many couples experience declines in relationship satisfaction in the early years of marriage, and such declines predict not only relationship dissolution but also poor mental and physical health.

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Evidência de um papel da oxitocina nos efeitos de ligação social da gratidão expressa.

# data[].attributes.attachment_link.title
Evidence for a role of the oxytocin system, indexed by genetic variation in CD38, in the social bonding effects of expressed gratitude

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Oxytocin is thought to play a central role in promoting close social bonds via influence on social interactions. The current investigation targeted interactions involving expressed gratitude between members of romantic relationships because recent evidence ...

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doi: 10.1038/s41598-021-82307-z.

Affiliations

¹ Department of Psychological Science, University of Arkansas, 216 Memorial Hall, Fayetteville, AR, 72701, USA. ammakhan@uark.edu.

² Department of Psychology, Florida State University, 1107 W. Call St, Tallahassee, FL, 32306, USA.

³ Department of Psychology, McGill University, 2001 McGill College Ave, Montreal, QC, H3A 1G1, Canada.

Free PMC article

Free PMC article

doi: 10.1038/s41598-021-82307-z.

Affiliations

¹ Department of Psychological Science, University of Arkansas, 216 Memorial Hall, Fayetteville, AR, 72701, USA. ammakhan@uark.edu.

² Department of Psychology, Florida State University, 1107 W. Call St, Tallahassee, FL, 32306, USA.

³ Department of Psychology, McGill University, 2001 McGill College Ave, Montreal, QC, H3A 1G1, Canada.

Abstract

Although there are numerous benefits to having a satisfying romantic relationship, maintaining high levels of relationship satisfaction is difficult. Many couples experience declines in relationship satisfaction in the early years of marriage, and such declines predict not only relationship dissolution but also poor mental and physical health. Several recent studies indicate that genetic variation on the CD38 gene (CD38), at the single nucleotide polymorphism (SNP) rs3796863, is associated with cognitions and behaviors related to pair bonding; we thus leveraged longitudinal data from a sample of newlywed couples (N = 139 genotyped individuals; 71 couples) to examine whether rs3796863 is associated with relationship maintenance processes and, in turn, relationship satisfaction in the early years of marriage. Replicating and extending prior research, we found that individuals with the CC genotype (vs. AC/AA) of rs3796863 reported higher levels of gratitude, trust, and forgiveness and that trust mediated the association between rs3796863 and marital satisfaction. Moreover, the benefits conferred to CC individuals lasted over the first 3 years of marriage. To our knowledge, this is the first study to examine the link between variation in CD38 rs3796863 and marital functioning over time.

Conflict of interest statement

The authors declare no competing interests.

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References

Finkel EJ, Hui CM, Carswell KL, Larson GM. The suffocation of marriage: Climbing Mount Maslow without enough oxygen. Psychol. Inq. 2014;25:1-41. doi: 10.1080/1047840X.2014.863723. - DOI

Fitzsimons GM, Finkel EJ. Transactive goal dynamics. Psychol. Rev. 2015;122:648-673. doi: 10.1037/a0039654. - DOI - PubMed

Holt-Lunstad J, Smith TB, Layton JB. Social relationships and mortality risk: A meta-analytic review. PLoS Med. 2010;7:e1000316. doi: 10.1371/journal.pmed.1000316. - DOI - PMC - PubMed

Proulx CM, Helms HM, Buehler C. Marital quality and personal well-being: A meta-analysis. J. Marriage Fam. 2007;69:576-593. doi: 10.1111/j.1741-3737.2007.00393.x. - DOI

Robles TF, Slatcher RB, Trombello JM, McGinn MM. Marital quality and health: A meta-analytic review. Psychol. Bull. 2014;140:140-187. doi: 10.1037/a0031859. - DOI - PMC - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
CD38 is associated with bonding-relevant cognitions and relationship satisfaction over the first 3 years of marriage - PubMed

# data[].attributes.attachment_link.description
Although there are numerous benefits to having a satisfying romantic relationship, maintaining high levels of relationship satisfaction is difficult. Many couples experience declines in relationship satisfaction in the early years of marriage, and such declines predict not only relationship dissolut ...

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Oxitocina durante as fases iniciais de relações românticas

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Oxitocina durante as fases iniciais de relações românticas

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Oxytocin during the initial stages of romantic attachment: relations to couples’ interactive reciprocity - PubMed

# data[].attributes.attachment_link.description
Romantic relationships can have a profound effect on adults’ health and well-being whereas the inability to maintain intimate bonds has been associated with physical and emotional distress. Studies in monogamous mammalian species underscore the central role of oxytocin (OT) in pair-bonding and human…

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https://www.cdc.gov/genomics/resources/diseases/obesity/obesedit.htm

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﻿

What do genes have to do with obesity?

Obesity is the result of chronic energy imbalance in a person who consistently takes in more calories from food and drink than are needed to power their body's metabolic and physical functions. The rapidly rising population prevalence of obesity in recent decades has been attributed to an "obesogenic" environment, which offers ready access to high-calorie foods but limits opportunities for physical activity. The obesity epidemic can be considered a collective response to this environment. Obesity is an important public health problem because it increases the risk of developing diabetes, heart disease, stroke, and other serious diseases.

Even in an obesogenic environment, not everyone becomes obese. Before the genomic research era, studies of family members, twins, and adoptees offered indirect scientific evidence that a sizable portion of the variation in weight among adults is due to genetic factors. For example, a key study that compared the body mass index (BMI) of twins reared either together or apart found that inherited factors had more influence than childhood environment.external icon

One gene or many?

Rarely, obesity occurs in families according to a clear inheritance pattern caused by changes in a single gene. The most commonly implicated gene is MC4R, which encodes the melanocortin 4 receptor. Changes in MC4R that diminish its function are found in a small fraction (< 5%) of obese people in various ethnic groups. Affected children feel extremely hungry and become obese because of consistent overeating (hyperphagia). So far, rare variants in at least nine genes have been implicated in single-gene (monogenic) obesity.

In most obese people, no single genetic cause can be identified. Since 2006, genome-wide association studies have found more than 50 genes associated with obesity, most with very small effects. Several of these genes also have variants that are associated with monogenic obesity, a phenomenon that has been observed in many other common conditions. Most obesity seems to be multifactorial, that is, the result of complex interactions among many genes and environmental factors.

How do genes control energy balance?

The brain regulates food intake by responding to signals received from fat (adipose) tissue, the pancreas, and the digestive tract. These signals are transmitted by hormones-such as leptin, insulin, and ghrelin-and other small molecules. The brain coordinates these signals with other inputs and responds with instructions to the body: either to eat more and reduce energy use, or to do the opposite. Genes are the basis for the signals and responses that guide food intake, and small changes in these genes can affect their levels of activity. Some genes with variants that have been associated with obesity are listed in the Table.

Energy is crucial to survival. Human energy regulation is primed to protect against weight loss, rather than to control weight gain. The "thrifty genotype" hypothesis was proposed to help explain this observation. It suggests that the same genes that helped our ancestors survive occasional famines are now being challenged by environments in which food is plentiful year round.

How can this knowledge help public health?

Public health efforts to prevent obesity focus on strategies that promote healthy eating and encourage physical activity. These strategies are employed at the community level, for example by increasing the availability of healthy food and beverage choices in schools and other public service settings. Such strategies are successful when many individual people respond with positive behavior changes.

A systematic review of information about more than 200,000 adults found that carriers of the common FTO gene variant most consistently associated with obesity were able to reduce their risk through physical activity.external icon Knowing that one's actions can make a difference is important.

Some new directions

Epigenetics. Environmental exposures during critical periods of human development can cause permanent changes in a gene's activity without changing the sequence of the gene itself. Studying these "epigenetic" effects involves measuring chemical modifications of DNA, RNA, or associated proteins that influence gene expression. Although epigenetics might help explain how early exposures such as infant feeding influence adult obesity, epidemiologic studies using these techniques are still at an early stage.

Gene symbol

Gene name

Gene product's role in energy balance

For additional information about genes that have been studied for association with obesity, visit the HuGE Navigator.

Additional reading:

Links

Centers for Disease Control and Prevention

Other health organizations

For more information on obesity and genomics for consumers, please see our Genomic Resources Guide.

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Obesity is the result of chronic energy imbalance in a person who consistently takes in more calories from food and drink than are needed to power their body's metabolic and physical functions. The rapidly rising population prevalence of obesity in recent decades has been attributed to an "obesogenic" environment, which offers ready access to high-calorie foods but limits opportunities for physical activity.

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Alteração no gene CD38 influencia a capacidade de demonstração de afeto

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Alteração no gene CD38 influencia a capacidade de demonstração de afeto

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https://veja.abril.com.br/ciencia/variacao-no-dna-esta-associada-a-capacidade-de-demonstrar-afeto/

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"Apaixonar-se por alguém está longe de ser a maior bobagem que as pessoas podem fazer - mas a força da gravidade não pode ser responsabilizada por isso." A frase, do físico alemão Albert Einstein (1879-1955), mostra como o amor, e as relações que fazem com que o sentimento floresça entre os apaixonados, permeia todos os campos, desde o trabalho do mais famoso dos cientistas até o subjetivo mundo das artes, como longas-metragens açucarados, extensos capítulos de romances e a composição de canções que se tornam trilhas sonoras de uma vida a dois. O beijo emoldurado pelo pôr do sol que ilustra esta reportagem pode ser apenas uma cena piegas para alguns, mas para os enamorados ela surge como uma lembrança de suas próprias paixões. Na vida real, o que explica aquela sensação de frio na barriga quando realmente gostamos de alguém? O que está por trás dos corações apaixonados? Por mais que as respostas para essas perguntas sejam na maioria dos casos inconclusivas, a ciência traz algumas pistas. Além de particularidades emocionais e psicológicas de cada um, como resultado do acúmulo de experiências ao longo da vida, a facilidade ou a dificuldade para se relacionar afetivamente com outra pessoa podem estar associadas ao DNA.

Pela primeira vez, pesquisadores canadenses identificaram a presença de uma variável genética no gene CD38 como fator que torna mais natural a habilidade de demonstrar afeto e apoio ao parceiro, assim como ter uma percepção mais positiva sobre as ações dele. Em contrapartida, os voluntários com outras variantes genéticas tiveram mais dificuldade para demonstrar afeto de forma natural e espontânea.

A explicação pode estar relacionada a traços evolutivos que garantiram a própria continuidade da espécie. "Relações próximas são decisivas para a sobrevivência humana", diz a psicóloga canadense Jennifer Bartz, da Universidade McGill. "Os mecanismos biológicos podem ter se desenvolvido em humanos para favorecer a criação de vínculos." É sabido que o bem-estar proporcionado por relações amorosas contribui para a saúde e até para o aumento da expectativa de vida dos indivíduos. Em outros animais, como roedores, estudos já haviam comprovado que a ocitocina, liberada pelo CD38, tem um papel relevante na conexão entre aqueles animais. Agora, os pesquisadores mostraram a mesma relação entre humanos.

Para coletar os dados, 111 casais participaram do estudo. Cada pessoa completou um formulário separadamente, com a orientação de não discutir as respostas com o parceiro. Os casais selecionados estavam juntos há no mínimo seis meses, não tinham crianças morando no mesmo lar e possuíam emprego fixo. Durante o período da pesquisa, os participantes descreveram até três interações diárias de ao menos cinco minutos com o parceiro. Para identificarem as nuances, os cientistas indicaram alguns comportamentos, como "sorri e dei risada", "fiz um comentário sarcástico", "pedi que o outro fizesse algo", ou "eu cedi". A noção de afeto foi medida de acordo com sentimentos negativos, como frustração, raiva e tristeza, e positivos, como felicidade, satisfação e diversão. Todos os participantes fizeram testes de DNA, e assim as informações foram cruzadas para identificar a predominância de determinada variação genética em certos tipos de comportamento.

Outros estudos também encontraram evidências entre características genéticas e o amor. Pesquisadores da Universidade de Pequim elucidaram a relação entre variantes do gene 5-HT1A e o estado matrimonial de seus portadores, concluindo que há uma relação significativa entre portar a forma genética CC e estar em um relacionamento duradouro. Ou seja: existem evidências científicas entre características biológicas e a probabilidade de ter um parceiro amoroso sério. Para a ciência, está muito claro que as variáveis genéticas são pequenas peças dentro de um enorme quebra-cabeça sobre a complexidade das relações interpessoais. O estudo canadense, por exemplo, mostrou que, além da maior facilidade para se conectar com outras pessoas, indivíduos com a variação CC se sentiram mais satisfeitos com a própria relação. Já aqueles com as características AA ou AC podem agir da mesma maneira, mas o processo não é tão espontâneo.

Além do risco de buscar uma explicação única para aquilo que atormenta as pessoas que tiveram o coração partido (afinal, por que meu romance não deu certo?), há uma discussão ética sobre a possibilidade de fazer testes genéticos em indivíduos que queiram encontrar sua cara-metade. No futuro, será que os aplicativos de encontros amorosos vão incluir informações genéticas ao lado de dados como profissão, preferência musical e hobbies? É improvável. O histórico das pessoas e as condições de vida interferem nas relações, inquestionavelmente. De forma prática, ter a informação sobre uma característica genética que traz efeitos positivos pode ser um norte para auxiliar os apaixonados. Mas isso não é tudo. Com ou sem os resultados sobre o DNA, o companheirismo e a parceria são elementos definidores para o sucesso no amor. E que seja infinito enquanto dure.
Publicado em VEJA de 2 de setembro de 2020, edição nº 2702

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Variação no DNA está associada à capacidade de demonstrar afeto

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"Apaixonar-se por alguém está longe de ser a maior bobagem que as pessoas podem fazer - mas a força da gravidade não pode ser responsabilizada por isso."

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Efeitos da oxitocina em relacionamentos e na vida social como um todo

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Efeitos da oxitocina em relacionamentos e na vida social como um todo

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https://mood.sapo.pt/afinal-ser-mais-ou-menos-sociavel-esta-nos-nossos-genes/

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Investigadores de Singapura descobriram que os genes CD38 e CD157, que regulam a oxitocina presente no corpo, também desempenham um papel importante na capacidade social de cada indivíduo.

Um grupo de investigadores da Universidade Nacional de Singapura descobriu que os adultos jovens que possuem maior expressão do gene CD38 e diferenças na sequência de genes do CD157 são mais amigáveis e mais socialmente ativos do que outros. No fundo, têm mais amigos próximos e mostram mais habilidades sociais.

Os genes CD38 e CD157 regulam a liberação de oxitocina, a hormona envolvida em comportamentos sociais primários, como a atração, o acasalamento e a criação de filhos, bem como em comportamentos mais sofisticados, como a empatia, a confiança e a generosidade. Este novo estudo sobre expressão genética, ou seja, o quanto de um gene específico é produzido no corpo, sustenta a importância crescente da oxitocina e do seu impacto na formação de habilidades sociais e de comunicação. As descobertas foram publicadas na revista científica 'Psychoneuroendocrinology'.
Veja também: Os diferentes tipos de amigos: qual é o seu perfil?
A equipa estudou 1300 jovens estudantes, nomeadamente a correlação entre a expressão do gene CD38 e a sequência do gene CD157, bem como as suas habilidades sociais através de três questionários diferentes. Esses questionários avaliaram a capacidade geral de os participantes estabelecerem relações sociais, o valor que têm para si, bem como o número de amigos e confidentes que têm.

Os resultados do estudo mostraram que os participantes com maior expressão de CD38 têm mais amigos íntimos, e esta associação foi observada com maior prevalência entre os participantes do sexo masculino. "Os participantes com expressões genéticas maiores apresentaram maior sociabilidade, preferindo atividades envolvendo outras pessoas a estarem sozinhas, e também melhores habilidades de comunicação e empatia em relação aos outros participantes. Enquanto isso, os participantes com menor expressão de CD38 relataram menos habilidades sociais, como dificuldade em "ler entre linhas" ou menor interação em conversas sociais, e tendem a ter menos amigos", explica Anne Chong, autora do estudo.

Curiosamente, os investigadores descobriram que uma variação na sequência do gene CD157, mais comum em casos de autismo segundo um estudo prévio japonês, também estava associada ao interesse inato dos participantes em socializar e construir relacionamentos.
Veja também: As vantagens de ter amigos no trabalho
Este estudo sugere que a oxitocina e os genes CD38 e CD157 que regem a sua liberação contribuem para as diferenças individuais nas habilidades sociais, entre um extremo de envolvimento social intenso e outro extremo que evita contatos sociais com outras pessoas, que é uma das características do autismo. Não há, no entanto, motivo de preocupação, segundo os pesquisadores, pois estes referem que a maioria das pessoas está entre os dois extremos.

Os pesquisadores descobriram que uma maior expressão do gene CD38 e as diferenças na sequência do gene CD157 representam 14% para a variação nas capacidades sociais na população em geral - uma percentagem notável e muito superior a outras influências genéticas no comportamento que se ficam em média pelos 2%, segundo os investigadores. "Porém, tal como a expressão dos genes pode influenciar os nossos comportamentos, também as nossas próprias experiências podem influenciar. Então, isto também depende muito dos nossos ambientes sociais. Para a maioria das pessoas, estar em ambientes sociais saudáveis, como ter famílias amorosas e solidárias, amigos e colegas, provavelmente reduzirá os efeitos destes genes", explica a investigadora.

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Afinal, ser mais ou menos sociável está nos nossos genes

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Investigadores de Singapura descobriram que os genes CD38 e CD157, que regulam a oxitocina presente no corpo, também desempenham um papel importante na capacidade social de cada indivíduo. Um grupo de investigadores da Universidade Nacional de Singapura descobriu que os adultos jovens que possuem maior expressão do gene CD38 e diferenças na sequência de genes do CD157 são mais amigáveis e mais socialmente ativos do que outros.

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https://www.vittude.com/blog/ocitocina/ outros efeitos e funções (maioritariamente benéficos) da oxitocina no organismo

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Ocitocina, também chamada de oxitocina, é um hormônio produzido pelo hipotálamo e liberado a partir da neuro-hipófise na corrente sanguínea. São encontrados receptores de ocitocina em células de todo o corpo.

Esse hormônio exerce importantes funções no organismo e nas sensações de prazer e afeto. Por esse motivo, também é conhecido como o "hormônio do amor".

Junto com a dopamina, a serotonina e a endorfina, a ocitocina faz parte do grupo chamado de "neurotransmissores da felicidade". Eles possuem a função de aumentar as sensações de bem-estar e diminuir estresse, ansiedade e melhorar quadros depressivos.

Nesse artigo, descubra os efeitos que o hormônio do amor proporciona ao nosso cérebro e corpo.

Efeitos físicos e psicológicos do hormônio do amor

De acordo com a Associação Americana de Psicologia, os níveis de ocitocina tendem a ser maiores durante experiências estressantes e ligadas ao convívio social. Isso quer dizer que o hormônio influencia o nosso comportamento, a criação de memórias, o reconhecimento, o apego, a generosidade, a empatia, entre outros comportamentos ligados às interações sociais.

Muitas pesquisas foram realizadas sobre os efeitos da ocitocina ao longo dos anos, sendo estudadas, inclusive, a sua capacidade de suprimir distúrbios mentais.

Foram constatados diversos efeitos benéficos, entre eles:

1. Facilita o parto normal

Uma das funções mais conhecidas do hormônio é o importante papel que desempenha no momento do parto.

Durante o trabalho de parto, o nível de ocitocina no organismo da mãe é extremamente aumentado. Ela age estimulando as contrações uterinas de forma regulada e abrindo o colo do útero, para facilitar a passagem do bebê pelo canal vaginal.

Após o nascimento do bebê, a ocitocina continua agindo no organismo da mulher, nas contrações uterinas, para diminuir a hemorragia.

Quando o hormônio não é liberado em quantidade suficiente pelo organismo, o obstetra pode solicitar o uso de medicamentos à base de ocitocina sintética para ajudar nessa função.

2. Importante para a amamentação

Na amamentação, a ocitocina também é fundamental. Através da sucção feita pelo bebê, são provocados impulsos elétricos no seio da mãe que vão até o cérebro, estimulando a liberação do neurotransmissor. Em seguida, o hormônio segue pela corrente sanguínea e vai até às glândulas mamárias, empurrando o leite pelos ductos.

O bebê ingere a ocitocina pelo leite materno e, juntando à que é produzida pelo contato entre mãe e filho, o vínculo entre ambos é reforçado.

3. Promove apego entre pais e filhos

Os benefícios não ficam restritos apenas à mãe biológica e o filho, mas também à mãe adotiva e ao pai (sendo biológico ou adotivo).

Com relação à mãe biológica, estudos indicam que mães que produziram maior quantidade de ocitocina durante o primeiro trimestre de gravidez, se envolvem mais afetuosamente com o bebê, levando a ações como cantar, tocar, cuidar da higiene e alimentação de forma mais carinhosa e específica.

Referente à paternidade e às mães e pais adotivos, estudos constataram que o envolvimento real e carinhoso com a criança, estimula a liberação de ocitocina, fortalecendo o vínculo.

4. Aumenta o prazer sexual

A ocitocina é liberada durante a relação sexual, tanto nos homens quanto nas mulheres.

Durante o orgasmo feminino, a ocitocina promove contrações uterinas. Nos homens, ocorre contrações dos ductos seminais e favorece a ejaculação.

A ocitocina intensifica a ligação entre parceiros sexuais.

5. Melhora das habilidades sociais

A ocitocina melhora significativamente a capacidade de as pessoas interagirem uma com as outras. Pacientes com autismo e esquizofrenia demonstram maior facilidade nas interações sociais quando a ocitocina é liberada.

Como a ocitocina está ligada ao desenvolvimento de confiança, os indivíduos passam a ter mais segurança ao se aproximar de outras pessoas. As percepções das expressões emocionais e sensibilidade também são beneficiadas.

6. Reduz o desejo por drogas

O desejo por drogas é reduzido com a liberação de ocitocina. De acordo com um artigo de 1999 do Progress in Brain Research, uma série de livros científicos, a ocitocina inibe a tolerância a drogas viciantes, como cocaína e álcool, e reduz os sintomas comuns de abstinência.

7. Alivia o estresse

O hormônio regula as emoções e o humor, favorecendo à diminuição do estresse. Essas adequações também são capazes de diminuir sintomas de depressão, ansiedade e fobia social.

A ocitocina possui efeito calmante, contrariando os efeitos do hormônio cortisol, conhecido por ser o hormônio do estresse.

8. Induz o sono

Com o cérebro livre de condições de estresse e ansiedade, o sono é naturalmente beneficiado. A ocitocina aumenta a sensação de tranquilidade e isso propicia o descanso e um eficiente sono reparador, fundamental para uma boa qualidade de vida.

9. Promove a generosidade

A ocitocina é capaz de afetar o senso de altruísmo, tornando as pessoas mais generosas. Inclusive, é uma via de mão dupla, quanto mais atos de generosidade o indivíduo pratica, mais libera ocitocina de forma natural no organismo. E assim, a prática de generosidade e trabalhos voluntários são estimulados.

10. Fortalece os relacionamentos amorosos

Nos relacionamentos amorosos, a liberação de ocitocina é estimulada através do contato físico, olhares, beijos, abraços e carinhos. Esse aumento da presença do hormônio do amor no organismo eleva as sensações de bem-estar e felicidade.

A ocitocina também é relacionada com a fidelidade. Estudos indicam que esse estímulo do hormônio durante os relacionamentos amorosos, faz com que as pessoas não se sintam atraídas por outros indivíduos que não sejam os seus parceiros.

Funciona como um sistema de recompensa, se o indivíduo sente prazer e felicidade com o seu parceiro, não busca procurar essas sensações fora do seu relacionamento. É esse sistema de recompensa que, de fato, fideliza os relacionamentos amorosos.

A ocitocina nos homens

O hormônio influência o comportamento e fisiologia de homens e mulheres. Porém, a ocitocina age de maneira diferente no homem e na mulher.

Além de situação específicas, como parto, amamentação e orgasmo feminino, enquanto que nos homens ocorre o estímulo da ejaculação e aumento do volume de esperma, outros efeitos são observados nos homens.

Ocorre também o aumento de hormônios anabolizantes, como a testosterona e relaxamento muscular, diminuindo sintomas de fibromialgia e hipertensão arterial.

O hormônio pode desempenhar um papel na maneira como homens identificam relações competitivas e atravessam momentos de luta e fuga.

Efeitos negativos da ocitocina

Apesar de todos os efeitos positivos da ocitocina e de sua função em estimular o apego e afeto entre os indivíduos, estudos indicam que a ocitocina também pode incentivar o favoritismo e preconceito, levando a formação de grupos e segregações.

Medicamento: Ocitocina sintética

A ocitocina sintética é semelhante à ocitocina natural. O fármaco pertence a um grupo de medicamentos chamado de ocitócicos.

O medicamento ocitocina é administrado para promover a contração uterina durante o parto normal, quando o corpo da mulher não produz o hormônio em quantidade suficiente ou para estimular a sua produção.

Nos partos cesáreas, o fármaco é utilizado para ajudar nas contrações uterinas que cessam o sangramento, evitando hemorragias.

A ocitocina em forma de medicamento também pode ser prescrita para ajudar na amamentação, enviando sinais às glândulas mamárias para liberação do leite materno.

Devido a sua capacidade de melhorar o humor e diminuir a sensação de estresse e ansiedade, o psiquiatra pode prescrever o uso de ocitocina em forma de medicamento para melhorar os sintomas de quadros psicológicos, como depressão, transtorno de ansiedade generalizada e fobia social.

Reações adversas do medicamento ocitocina

Como qualquer medicamento, o uso de ocitocina sintética pode causar alguns efeitos colaterais. Nem todas as pessoas apresentam reações adversas, mas as mais comuns são:

Dor de cabeça;

Batimentos cardíacos acelerados (taquicardia);

Batimentos cardíacos lentos (bradicardia);

Náusea;

Vômitos.

Quando utilizado para estimular a amamentação, pouca quantidade de ocitocina é excretada junto ao leite. Em geral, essa quantidade não é prejudicial ao bebê, pois rapidamente perde o seu efeito. Porém, é necessário se atentar e, em caso de alguma reação incomum, procurar o médico imediatamente.

Alimentos que estimulam a liberação da ocitocina

Alguns alimentos são capazes de estimular a liberação de ocitocina e outros hormônios que produzem sensações de bem-estar, felicidade e bom humor, como a serotonina.

Os alimentos eficientes para essa função, incluem:

Chocolate;

Oleaginosas, como castanhas, avelã e pistache;

Banana;

Folhas verde-escuras;

Proteínas, especialmente ovos e frutos do mar;

Leite.

Sinais de que a ocitocina está em falta no organismo

As pessoas que produzem o hormônio em quantidade inadequada, apresentam instabilidades mentais e físicas. Os principais sintomas que indicam uma diminuição do neurotransmissor no organismo, são:

Palidez;

Olhar triste;

Dificuldade em sorrir;

Olhos secos;

Falta de expressões emocionais;

Estresse;

Diminuição da libido;

Diminuição da função cognitiva;

Diminuição da memória e atenção;

Distúrbio do sono;

Falta de lubrificação durante o sexo;

Diminuição da capacidade de ejacular;

Diminuição da capacidade de chegar ao orgasmo, nas mulheres;

Obesidade;

Frieza ao demonstrar sentimentos;

Tensão e dores musculares;

Excesso de sensibilidade a dor;

Incapacidade de amamentar, mesmo quando os seios estão cheios de leite;

Ansiedade e medo excessivos.

Esses sintomas também são relacionados a outros distúrbios mentais e psicológicos. Por isso, fique atento e procure um médico ou um psicólogo para diagnóstico e tratamento adequados.

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Ocitocina: 10 efeitos interessantes do hormônio do amor - Blog Vittude

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Ocitocina, também chamada de oxitocina, é um hormônio produzido pelo hipotálamo e liberado a partir da neuro-hipófise na corrente sanguínea. São encontrados receptores de ocitocina em células de todo o corpo. Esse hormônio exerce importantes funções no organismo e nas sensações de prazer e afeto.

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LINK para o padlet da questão de investigação

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LINK para o padlet da questão de investigação