Replication of a Novel Parkinson's Locus in a European Ancestry Population

Abstract

Background: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.Objectives: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. Methods: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. Results: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD P European = 6.64 × 10 −4 , pooled PD P = 1.15 × 10 −11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10 −8 ). Conclusions: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed.

The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

“…Other top hits included proteins previously tied to aS, vesicle trafficking. and PD biology, such as VapA, VapB (Paillusson et al, 2017), and Sv2c (Bereczki et al, 2018;Dunn et al, 2017;Grover et al, 2021).…”

Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology

“…However, they are not enriched in endocytic proteins and in several house-keeping SV proteins, consistent with the lack of enrichment of SVs in these terminals, although they are enriched in SV2C, raising the possibility that this SV protein may remain stranded in the plasma membrane. Interestingly, SV2C, which is the SV2 family member expressed in DAergic neurons and is a modulator of DA release 29 , was recently identified by GWAS from both Asian and European cohorts as a PD candidate risk gene 31,32 . Moreover, in both mutant genotypes, presence of these structures peak at 1-2 months but they decrease as mice get older (5 and 12 months), revealing either repair mechanisms or removal of degenerated nerve terminals in older mice.…”

Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice

“…S9), indicating the core role of behavioral modification in mice domestication. Worthy of mention is that some PSGs without known behavioral phenotypes are associated with human mental illnesses, e.g., CBLN4 (Alzheimer's disease [33]), WBSCR17 (Parkinson's disease [34,35], autism [36]), and ASTN2 (autism [37][38][39][40][41][42], Alzheimer's disease [43,44], intellectual disability [45,46], schizophrenia [47,48], and attention deficit/hyperactivity disorder [40,[49][50][51]).…”