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Whole Genome Sequencing (WGS): information about variant genetic sequences were stored in VCF files. That were extracted from the Parkinson’s Progression Markers Initiative database for P450s, POR, Adx and AdR and genetic variants were identified.

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Adrenodoxin is an iron-sulfur protein that belongs to the broad family of the [2Fe-2S]-type ferredoxins found in plants, animals and bacteria. Its primary function as a soluble electron carrier between the NADPH-dependent adrenodoxin reductase and several cytochromes P450 makes it an irreplaceable component of the steroid hormones biosynthesis in the adrenal mitochondria of vertebrates.

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FAD containing flavoprotein that functions as an electron transfer protein in the mitochondrial P450 systems that catalyze essential steps in the biosynthesis of steroid hormones.

Image source: https://proteopedia.org/wiki/index.php/Adrenodoxin_reductase

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Identification of 57 cytochromes P450

GUN vs. HC

26 SNPs + 3 redox partners with OR<5

18 SNPs + AdR with OR>0.2

GPD vs. HC

31 cytochromes P450 + AdR and Adx with OR<5

23 cytochromes P450 + AdR with OR>0.2

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Overview

Parkinson disease (PD) is a brain condition that causes problems with movement, mental health, sleep, pain and other health issues.

PD gets worse over time. There is no cure, but therapies and medicines can reduce symptoms. Common symptoms include tremors, painful muscle contractions and difficulty speaking.

Parkinson disease results in high rates of disability and the need for care. Many people with PD also develop dementia.

The disease usually occurs in older people, but younger people can also be affected. Men are affected more often than women.

The cause of PD is unknown but people with a family history of the disease have a higher risk. Exposure to air pollution, pesticides and solvents may increase risk.

Symptoms

Symptoms of Parkinson disease get worse over time. They can greatly reduce well-being and quality of life.

PD causes motors symptoms including:

Non-motor symptoms:

cognitive impairment

mental health disorders

dementia

sleep disorders

pain

sensory disturbances.

Involuntary movements (dyskinesias) and painful muscle contractions (dystonias) can cause problems speaking and moving. These symptoms lead to high rates of disability and the need for care. Many people with PD also develop dementia during the course of their disease.

While PD is the most common movement disorder, other movement disorders exist such as multiple system atrophy, progressive supranuclear palsy, chorea, ataxia and dystonia. Some movement disorders have similar symptoms to PD such as tremor, slow movement and rigidity. All movement disorders share the same challenges as PD regarding diagnostic and treatment gaps and access to medication, particularly in low- and middle-income countries (LMIC).

Assessment and disease burden

PDis a clinical diagnosis that not only can be made by neurologists but also by trained non-specialist healthcare workers. Assessment and management of PD by trained non-specialized healthcare workers in primary care is particularly important in areas where specialist neurological services are unavailable, such as in some LMIC.

The prevalence of PD has doubled in the past 25 years. Global estimates in 2019 showed over 8.5 million individuals with PD. Current estimates suggest that, in 2019, PD resulted in 5.8 million disability adjusted life years (DALYs), an increase of 81% since 2000, and caused 329 000 deaths, an increase of over 100% since 2000.

Treatment and care

There is no cure for Parkinson disease, but therapies including medicines, surgery and rehabilitation can reduce symptoms.

Levodopa/carbidopa, a combination medicine that increases the amount of dopamine in the brain, is the most common medication for PD (1). Doctors may use other medicines such as anticholinergics to reduce involuntary muscle movement.

Deep brain stimulation and other therapies can help the tremors and reduce the need for medicines.

Rehabilitation including physiotherapy can offer relief for Parkinson disease and other degenerative neurologic disorders. Therapies include:

strength training

gait and balance training

hydrotherapy.

These therapies can help improve functioning and quality of life for people with PD. This can also reduce the strain on carers.

Many medications and surgical resources are not accessible, available or affordable everywhere, particularly low- and middle-income countries.

Impact on families and carers

Informal carers (i.e. most commonly family members and friends) spendmany hours dailyproviding care for people living with PD.This can be overwhelming. Physical, emotional and financial pressures can cause great stress to families and carers, and support is required from the health, social, financial and legal systems. Useful support resources from other conditions can be drawn upon, such as WHO's iSupport programme for dementia.

Human rights

People with PD are often subject to stigma and discrimination, including unjust discrimination within the workplace and lack of opportunities to engage and participate in their communities.

People with PD require accessible health services for general healthcare needs like the rest of the population, including medicine access, promotive and preventive services and prompt diagnosis, treatment and care. A common barrier is created by healthcare providers' inadequate knowledge and understanding of PD and myths that PD is a contagious illness or a normal part of aging.

WHO response

In May 2022, the World Health Assembly endorsed the Intersectoral global action plan on epilepsy and other neurological disorders 2022-2031. The action plan will address the challenges and gaps in providing care and services for people with epilepsy and other neurological disorders such as PD that exist worldwide and ensure a comprehensive, coordinated response across sectors. This includes raising policy prioritization and strengthening governance, providing effective, timely and responsive diagnosis, treatment and care, implementing strategies for promotion and prevention, fostering research and innovation and strengthening information systems.

A WHO technical brief entitled Parkinson disease: a public health approach is available for policy-makers, health programme managers and planners, healthcare providers, researchers, people with PD, carers and other stakeholders. It outlines the important action areas for intervention in PD including global health policies focused on prevention and risk reduction, education and awareness and access to treatment and care at various levels of the health system.

WHO's iSupport, a knowledge and skills training programme for carers of people living with dementia is available as an online course and a hardcopy manual. iSupport Lite includes easy-to-read posters and a brief video that can act as a quick reference or a refresher, reinforcing previously acquired caregiving skills and knowledge.
Notes
Levodopa/carbidopa is on the WHO Model List of Essential Medicines.

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Parkinson disease (PD) is a degenerative condition of the brain associated with motor symptoms (slow movement, tremor, rigidity, walking and imbalance) and a wide variety of non-motor complications (cognitive impairment, mental health disorders, sleep disorders and pain and other sensory disturbances).

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Centers for Common Disease Genomics (CGDG)

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Centers for Common Disease Genomics (CGDG)

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CCDG are a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes.

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The CCDG initiative explores a range of diseases with the goal of:

Undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of genomic architecture underlying common, complex inherited diseases.

Understand how best to design rare variant studies for common disease.

Develop resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community.

The CCDGs study cardiovascular diseases (early-onset cardiovascular disease, atrial fibrillation, hemorrhagic stroke), neuropsychiatric diseases (autism, Alzheimer's disease, epilepsy), and immune-mediated diseases (irritable bowel disorder, asthma, Type-1 diabetes). CCDG studies have been limited to the nine selected diseases to increase study power.

The CCDGs collaborate with other projects, including the National Heart Lung and Blood Institute (NHLBI) Trans-omics for Precision Medicine program. The centers also receive co-funding from NHLBI.

We currently estimate that the CCDG program will sequence approximately 100K whole genomes and 125K whole exomes during the life of the program.

More information on the CCDGs, including publications, can be found on the Coordinating Center managed website: http://ccdg.rutgers.edu/.

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A collaborative large-scale genome sequencing effort to identify rare risk and protective variants contributing to multiple common disease phenotypes.

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Area of ​​great interest in the development of neuroscience research.

Some mechanisms of several complex neurological diseases, such as Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS) and psychiatric disorders, have been decoded through technological advances.

Thus, an interconnection was established between hereditary and non-hereditary mutations, epigenetics and other factors that require genomic tools to understand these diseases.

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Group of enzymes encoded by P450 genes and are expressed as membrane bound proteins mostly found in the endoplasmic reticulum of the liver. CYP enzymes function as monoxygenases and effect oxidation by transfer of one oxygen atom through a number of steps.

Image source: https://en.wikipedia.org/wiki/Cytochrome_P450

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Individuals with genetic predisposition to Parkinson's disease, suffering from the disease

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Individuals with genetic predisposition forParkinson's disease but without symptoms of the disease.

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Biologia do Genoma

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Luís Souto

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Alexandra Rito, nº 103438

Amélia Graça, nº 102559

Joana Passos, nº 103894

Maria Loura, nº 89866

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Measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure.

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A landmark study collaborating with partners around the world to create a robust open-access data set and biosample library to speed scientific breakthroughs and new treatments.

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Home | Parkinson’s Progression Markers Initiative

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Robust, real-time PPMI data is open access to speed breakthroughs and support validation.

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Enzyme that plays a pivotal role in numerous metabolic processes, notably facilitating reactions catalyzed by cytochrome P450 proteins involved in metabolizing steroid hormones, drugs, and xenobiotics.

Image source: https://www.sciencedirect.com/science/article/abs/pii/B9780128096338040401

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Genomic variant at a single base position in the DNA.

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Provides a deep insight into the DNA sequence of humans, animals, plants, and microbial genomes, with data analysis at the individual or population level. Sequencing analysis enables the identification of somatic and germline mutations as well as customized patterns of cancers and other diseases.

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Conducting experimental studies examine the consequences of the SNPs identified in this study.

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Identification of 7 SNPs and AdR with no significant differences

Identification of 3 cytochromes P450 with OR>10 (CYP4V2, CYP24A1, CYP39A1)

SNPs(GPD/GUN) < SNPs(GUN/HC) and SNPs(GPD/HC)

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SNPs with OR>5

Metabolisms: fatty acids, eicosanoids, vitamins, sterols

SNPs with OR<0.2

Metabolisms: fatty acids, eicosanoids, vitamins, sterols, drugs and xenobiotics

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No SNPs over-represented (OR>5)

No SNPs with OR<0.2

1 SNP with 2.0<OR<5.0

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SNPs with OR>5 (CYP7B1, CYP39A1)

6 SNPs with 2.0<OR<5.0 (CYP46A1)

High-OR SNPs with unknown function

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SNPs with OR>5 (CYP24A1, CYP26B1, CYP27C1)

5, 3 and 26 SNPs with 2.0<OR<5.0

SNP highly protective (OR<0.2, CYP27C1)

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No SNPs with OR>5

Except 7 of the total cytochromes P450 (CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C18, CYP2F1, CYP3A4) do not have 2.0<OR<5.0

SNPs with OR<0.2 (CYP2C8)

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SNPs with OR>5 (CYP4F3, CYP4F8, CYP8A1)

SNPs with 2.0<OR<5.0 (CYP4F2, CYP4F3, CYP5A1, CYP8A1)

82 SNPs with 0.2<OR<0.5

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2 SNPs with OR>5 (modifier function)

2 SNPs with 2.0<OR<5.0

57 SNPs with 0.5<OR<2.0

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Up-represented in GPD and HC individuals

Important SNPs (CYP5A1, CYP2C8, CYP4F3, CYP4B1, POR)

Cytochrome P450 with a protective effect (SNPs with OR<1)

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1. “Rolf M. Schwiete Stiftung” Center in Mannheim/Germany and PPMI database: the research was granted by the center and was made possible through the access of data from the Parkinson’s Progression Markers Initiative (PPMI) database, wich has been supporting investigations worldwide.

2. PPMI data and Bioinformatics: the extraction and classification of the data from the PPMI database was performed by Prof. Dr. Andreas Keller and Dr. Tobias Fehlmann from Saarland clinical informatics campus, in cooperation with the research team.

3. Interdisciplinary research team consortia: the design, analysis and discussion of project data and results were performed by team members organized for different contributions.

4. The R project for statistical computing: programming language used for gene variants classification groups in this research ensured high-quality data.

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SnpEff and SnpSift 5.0: rapidly categorizing the effects of variants in genome sequences based on their genomic locations and predicts coding effects.

Software IBM® SPSS®: advanced statistic analysis. Suitable for projects of all sizes and levels of complexity.

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Parkinson's Progression Markers Initiative (PPMI) - obtain complete sequencing data for the genomes of P450, P450 reductase (POR), adrenodoxin (Adx), adrenodoxin reductase (AdR), and their genetic variants.

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All authors declared that the research was conducted without any commercial or financial affiliations that might pose a potential conflict of interest.

However, there’s no evident sign of a speciallized committe’s authentication on the fulfillment of the social and ethical laws on this article.

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Identifying and thoroughly characterizing the biochemical pathways influenced by the SNPs identified in this study is essential.

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Parkinson's disease potential novel targets

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Parkinson's disease potential novel targets

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Identification of potential novel targets for early diagnosis, intervention, and treatment of Parkinson's disease.

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Guengerich, F. P. Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions. Chem Res Toxicol 30, 2–12 (2017).

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Parkinson's disease (PD) is a neurodegenerative disease that affects millions of people around the world.

It affects an individual's movements, which can cause:

tremors

muscle stiffness

imbalance

slow movement

changes in speech and writing

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According to the WHO (World Health Organization), the prevalence of this disease has increased exponentially over the years, increasing by more than 100% in the last 25 years. However, the treatment of PD remains symptomatic, so research into early diagnosis through new biomarkers and the development of effective treatments continues.

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Previously, an article from this research group was published, which analyzed a possible association between the pathogenesis of PD and single nucleotide polymorphisms (SNPs) in cytochrome P450 (P450) genes (page 164).

Although the majority of cases of this disease have an unknown origin (idiopathic), around 5-10% are hereditary and related to mutations in different known genes and there are still people with a genetic predisposition to PD who do not develop the disease.

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CYP2D6, CYP2C9 and CYP3A4 show OR values between 1.4 and 2.9, while CYP2A6 and CYP2F1 display protective SNPs with OR < 1, in both GPD/HC and GPD/GUN.

Special attention should be given to CYP2C8, which displays 10 SNPs, though with moderate OR values, which are found in GPD/GUN and also in GPD/HC.

Summarizing, this suggests that toxic compounds, e.g., pesticides, seem to be of rather moderate importance for the manifestation of PD in genetically predisposed individuals.

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CYP4V2 shows a SNP with OR = 10.02 in GPD/GUN. It also shows two protective SNPs, that are under-represented in GPD/GUN and GPD/HC.

CYP4V2 is widely expressed in different organs and tissues, also in brain, and is described to show ω-hydroxylase activity on saturated and polyunsaturated fatty acids (PUFAs) of medium and long chain length.

A functional impairment of CYP4V2 leads to a malfunction of global lipid metabolism. Causing Reduction in the transformation of fatty acid precursors into w-3 PUFAs and decreased synthesis of eicosapentaenoic (EPA)(20:5) and docosahexaenoic acids (DHA)(22:6).

In view of the involvement of CYP4V2 in the metabolism of saturated and polyunsaturated fatty acids, we checked whether the consumption of fish oil and omega fatty acid supplements has an effect on the manifestation of GPD since for some individuals in the PPMI database corresponding information is available. Analysis of the data, however, didn't show any statistical significance, thus demonstrating no protective role of the oil on the manifestation of the disease.

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Analyzing the role of P450s of the “eicosanoid” group, our results show that P450s involved in eicosanoid metabolism and inflammation seem to have a key function in the manifestation of GPD.

CYP4F2, CYP4F3, CYP5A1 and CYP8A1 have SNPs with OR values between 2 and 5 in GPD/GUN and GPD/HC.

CYP5A1 is a tromboxane synthase and its function is related to the action of CYP8A1, a prostacyclin synthase. While both P450s use prostaglandin H2 (PGH2) as a substrate, prostacyclin (prostaglandin I2, PGI2), resulting from the catalytic action of CYP8A1, causes vasodilation, inhibits platelet aggregation. While thromboxane A2 (TXA2), resulting from the catalytic action of CYP5A1, causes vasoconstriction, promotes platelet aggregation.

The balance of the two products affects important physiological processes such as blood pressure regulation, blood coagulation and inflammation.

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Figure 1- The synthesis of vitamin D. Image obtained from “Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment”.

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CYP24A1 is one of the three P450s displaying a SNP with OR = 10.02 for GPD/GUN.

The SNP is located in an intron region and suggested to behave as a modifier of function. It is responsible for the degradation of 25OH- as well as 1α, 25- dihydroxy vitamin D3 to 24-hydroxylated products.

Changes in the expression and functionality of CYP24A1 may thus have broad consequences. First, malfunction could lead to an accumulation of the precursor 7- dehydrocholesterol and in this way to increased levels of cholesterol. On the other hand, an unbalanced high expression of CYP24A1 may lead to vitamin D deficiency thereby causing various disorders connected to bone metabolism, immunomodulation and proliferative disorders like cancer.

There is no effect of nutritional supplementation with vitamin D on the manifestation of PD in genetically pre-disposed individuals.

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Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment

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Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24

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Genomic Analysis Identifies New Loci Associated With Motor Complications in Parkinson’s Disease

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Sterol-converting P450s also show a strong association of SNPs in corresponding P450 genes with the manifestation of PD in GPD vs. GUN.

CYP39A1 is the third P450 found in our studies with an OR = 10.02 (GPD/GUN). This P450 plays a prominent role in the degradation of cholesterol. By using GWAS investigations it was reported that four intron variants of CYP39A1 (rs6907129, rs6905960, rs7749491, rs16874881) are strongly associated with the occurrence of levodopa-induced dyskinesia in patients aged over 50 years at the onset of PD.

CYP7B1 is another P450 gene having SNPs with OR values >5 in GPD/GUN. This P450 is also involved in the degradation of cholesterol leading to 7α-hydroxylation of 27-hydroxycholesterol.

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mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

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CYP20A1 belongs to the group of “orphan” P450s, displays SNPs with OR > 5 (GPD/GUN).

CYP20A1 is especially abundant in S. nigra and the hippocampus of human brain.

Thus, endogenous rather than exogenous factors seem to be responsible for the differentiation between GPD and GUN and inflammation, vitamin D metabolism, cholesterol degradation and pathways affected by CYP20A1 seem to be key players in eliciting PD manifestation.

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POR show SNPs with OR > 5 when comparing all SNPs between GPD and GUN.

Shows SNPs with OR < 0.2 in both approaches indicating on a contribution of this protein, which is the redox partner of all microsomal P450s, for the transformation from GUN to GPD.

This points to a possible modulatory effect of this redox partner on the manifestation of PD in GPD patients.

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1. Identification of single nucleotide polymorphisms (SNPs) within protein genes linked to the transition from individuals genetically predisposed to Parkinson's disease (PD) but asymptomatic (GUN) to those displaying symptoms of the disease (GPD).

2. Some of the SNPs are up-represented in GPD individuals, suggesting that they may have a role in the manifestation of Parkinson's disease, possibly through the "combination" of SNPs

3. The SNPs present in the fatty acids, eicosanoids, vitamins, and sterols metabolisms seem to have a better effect in the switch from GUN to GPD individuals.

4. Endogenous factors, such as inflammation, vitamin D metabolism, and cholesterol degradation and pathways, appear to be crucial factors in triggering the onset of Parkinson's disease symptoms.

5. In addition to harmful single nucleotide polymorphisms (SNPs) that are significantly more prevalent in patients with symptomatic Parkinson's disease (GPD), protective SNPs are equally significant. These protective SNPs, largely absent in GPD patients, are present in those who are genetically predisposed to Parkinson's disease but asymptomatic (GUN). The potential protective effect could play a significant role in slowing the progression of Parkinson's disease.

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Extraction of the data from the PPMI database

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Extraction of the data from the PPMI database

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Lists for the variants (P450s, POR, Adx, AdR) were obtained by downloading the whole-genome sequencing VCF files of the Parkinson’s Progression Markers Initiative, witch led to identification of biomarkers of progression in PD.

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These were generated based on whole-blood extracted DNA samples and processed with the Centers for Common Disease Genomics standard pipeline, with the human hg38 assembly as reference genome.

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Variants were annotated with SnpEff 5.0 

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Variants were annotated with SnpEff 5.0 

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Genetic variant annotation, and functional effect prediction toolbox. It annotates and predicts the effects of genetic variants on genes and proteins. Supports over 38,000 genomes.

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SnpSift annotates genomic variants using databases, filters, and manipulates genomic annotated variants.
Once annotated files with SnpEff, SnpSift can filter large genomic datasets in order to find the most significant variants for an experiment.

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Variants were further processed with the R programming language and classified in groups (IPD, GPD, GUN and HC) based on clinical diagnosis.

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Statistical analysis: IBM-SPSS Version 26/27 

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Statistical analysis: IBM-SPSS Version 26/27 

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Calculates corresponding odds ratios (OR) and confidence intervals (CI). Any p values reported are two-sided and subject to a significance level of 0.05.

Estimate the link between the occurrence of a particular SNP in the genes of the proteins and the incidence of P

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Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012 Apr-Jun;6(2):80-92. doi: 10.4161/fly.19695. PMID: 22728672; PMCID: PMC3679285.

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. 2012 Apr-Jun;6(2):80-92.

doi: 10.4161/fly.19695.

Affiliation

¹ Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA.

Pablo Cingolani et al. Fly (Austin).

. 2012 Apr-Jun;6(2):80-92.

doi: 10.4161/fly.19695.

Affiliation

¹ Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA.

Abstract

We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w(1118); iso-2; iso-3 strain and the reference y(1); cn(1) bw(1) sp(1) strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in the 5'UTR. We found, as expected, that the SNP frequency is proportional to the recombination frequency (i.e., highest in the middle of chromosome arms). We also found that start-gain or stop-lost SNPs in Drosophila melanogaster often result in additions of N-terminal or C-terminal amino acids that are conserved in other Drosophila species. It appears that the 5' and 3' UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus. As genome sequencing is becoming inexpensive and routine, SnpEff enables rapid analyses of whole-genome sequencing data to be performed by an individual laboratory.

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Platts AE, Land SJ, Chen L, Page GP, Rasouli P, Wang L, et al. Massively parallel resequencing of the isogenic Drosophila melanogaster strain w(1118); iso-2; iso-3 identifies hotspots for mutations in sensory perception genes. Fly (Austin) 2009;3:192-203. - PMC - PubMed

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McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297-303. doi: 10.1101/gr.107524.110. - DOI - PMC - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 - PubMed

# data[].attributes.attachment_link.description
We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, ups ...

# data[].attributes.body
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., … Ruden, D. M. (2012). A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff:  SNPs in the genome of Drosophila melanogaster strain w¹¹¹⁸; iso-2; iso-3. Fly, 6(2), 80–92. https://doi.org/10.4161/fly.19695

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The aim of this article was to study the factors that can lead to the manifestation of PD, comparing the occurrence of single nucleotide polymorphisms (SNPs) in several cytochrome P450 genes in people with predisposition and suffering from PD (GPD) and those people who are genetically predisposed but do not show symptoms of the disease (GUN).