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Human genetic variation and Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a chronic neurodegenerative disorder with multifactorial etiology. In the past decade, the genetic causes of monogenic forms of familial PD have been defined. However, the etiology and pathogenesis of the majority of sporadic PD cases that occur in outbred populations have yet to be clarified. The recent development of resources such as the International HapMap Project and technological advances in high-throughput genotyping have provided new basis for genetic association studies of common complex diseases, including PD. A new generation of genome-wide association studies will soon offer a potentially powerful approach for mapping causal genes and will likely change treatment and alter our perception of the genetic determinants of PD. However, the execution and analysis of such studies will require great care.

SUBMITTER: Chung SJ

PROVIDER: S-EPMC4027658 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Human genetic variation and Parkinson's disease.

Chung Sun Ju SJ

Journal of movement disorders 20100430 1

Parkinson's disease (PD) is a chronic neurodegenerative disorder with multifactorial etiology. In the past decade, the genetic causes of monogenic forms of familial PD have been defined. However, the etiology and pathogenesis of the majority of sporadic PD cases that occur in outbred populations have yet to be clarified. The recent development of resources such as the International HapMap Project and technological advances in high-throughput genotyping have provided new basis for genetic associa ...[more]

PMID: 24868370

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Project description:BackgroundMitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function.ObjectiveThe objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.MethodsWe employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions.ResultsUsing the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ).ConclusionsOur results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description:Background:The phospholipase A2 Group 6 (PLA2G6, also known as PLA2, PARK14, and iPLA2) gene encodes a group VIA calcium-independent phospholipase A2. Genetic polymorphism of PLA2G6 has been indicated to be involved in conferring susceptibility for Parkinson's disease (PD), whereas conclusive results have not been obtained. Thus, we intended to conduct a systematic review to determine if PLA2G6 genetic variation confers a greater susceptibility to PD. Methods:All case-control studies that investigated the association of the PLA2G6 polymorphisms with the risk of PD published before 15 July 2018 were included. The literature was comprehensively searched and identified in five English databases (EBSCO, Pubmed, OVID, EMBASE and ISI Web of Knowledge) and four Chinese databases (Wanfang database, Chinese Biomedical Literature Database, China Academic Journals Database and VIP database). We performed analyses of study characteristics, heterogeneity, and forest plot in analyses analogous to dominant, codominant and additive models with the pooled odds ratio (OR) in fixed- or random-effects models as the measure of association. Results:A total of 664 potentially relevant studies were retrieved with the initial search, of which eight studies fulfilled the inclusion criteria, and included 2,779 PD patients and 3,291 control participants,. Among all the reported 27 genetic variants, 15 single nucleotide polymorphisms (SNPs) were present only in patients, and only five available SNPs (rs2267369, rs140758033, c.1959T>A (Gly653Gly), rs76718524, rs199935023) were pooled in the meta-analysis. However, there was no evidence for a significant association between the five SNPs and PD risk in dominant, codominant and allele models, suggesting a lack of association between PLA2G6 genetic variation and PD susceptibility. Conclusion:The present study assessed the association of PLA2G6 genetic polymorphism with the risk PD, and the result strongly demonstrates that PLA2G6 polymorphism is not associated with PD susceptibility.

Dataset Information

Human genetic variation and Parkinson's disease.

Publications

Human genetic variation and Parkinson's disease.

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