The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci

Frontiers in Neurology

International Parkinson’s Disease Genomics Consortium¹  Carles Vilariño-Güell²  Sophie Imhoff³  Norbert Brüggemann³  Philip Seibler³  Elisabeth Luisa Germer³  Joanne Trinh³  Meike Kasten³  Christine Klein³ 

[1] ;Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada;Institute of Neurogenetics, University of Lübeck, Lübeck, Germany;

关键词: Parkinson's disease;    GWAS;    rare variants association analyses;    exome analysis;    STAB1;    SH3GL2;   

DOI  :  10.3389/fneur.2019.01284

来源: DOAJ

【 摘 要 】

Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation.Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort.Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10−3).Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk.

【 授权许可】

Unknown