Abstract
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.
Highlights
Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson’s disease (PD) risk
We studied exomes from 109 subjects who are from Germany, recruited in Lübeck (85 with PD and 24 healthy controls); 23 patients were known to carry either a pathogenic or likely pathogenic variant in genes described in PD [11] (i.e., PRKN, SNCA, PINK1, PLA2G6, GBA, LRRK2) (Supplementary Table 1)
Exome sequencing was performed on all 109 individuals, and exome variants located within the 56 GWAS PD loci were selected for further analysis [9, 10]
Summary
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. A substantial proportion of genetic influence on PD remains to be elucidated. Genomewide association studies (GWAS) in PD patients have identified genetic loci, which typically nominate regions of association but do not pinpoint causal variants. Both common and rare coding variants in SNCA and LRRK2 have been reported to be associated with PD. SNCA p.A53T was the first identified pathogenic mutation for PD [5], and subsequent GWAS nominated common risk
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