Objective: The aim of this study is to provide new insights into the genetic architecture of multiple system atrophy (MSA) and investigate shared molecular genetic mechanisms between MSA and Parkinson’s disease (PD).

Background: Despite the clinical overlap between PD and MSA, there have been conflicting results regarding the role of α-synuclein in MSA pathogenesis and recently published MSA GWAS failed to identify novel loci for its underlying pathogenesis. A genetic-pleiotropy approach was applied to identify novel loci in a diverse spectrum of complex diseases (1)

Method: We applied conditional/conjunctional false discovery rate method (condFDR/conjFDR) to genome-wide association study (GWAS) summary statistics data on MSA (1030 cases and 3864 controls) and PD (13,708 cases and 95,282 controls)(2,3). The genetic overlap between MSA and PD was assessed by conditional quantile-quantile (Q-Q) plots and LD-score genetic correlation. Functional annotation of the identified variants and pathway analysis were performed using FUMA.

Results: Conditional QQ plots (Figure 1A and 1B) showed a considerable genetic overlap between MSA and PD supported by significant genetic correlation (rg=0.5535, p=7.76E-03). We identified 8 MSA-associated loci at level condFDR<0.05 (Table 1, Figure 2) out of these hits four were not reported previously. The leading SNPs for 4 of these 3 novel loci are located in introns of protein coding genes (SLC2A5, ANO3 and RILPL2) and the latter is 43044 kb downstream of the RN7SKP141 gene. One shared locus between MSA and PD with the leading SNP in WNT3 gene was identified in conjFDR analysis (conjFDR<0.05). Pathway analysis of identified loci revealed significant enrichment in male genitalia development, carbohydrate transmembrane transport, establishment of protein localization to plasma membrane pathways (Figure 3).

Conclusion: Our study for the first time provided an evidence regarding the involvement of a common genetic component between MSA and PD and identifies 4 novel loci associated with MSA. Taken together, these findings may contribute towards a better understanding of genetic risk architecture of MSA and its relation to PD.

References: 1. Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C, et al. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol [Internet]. 2017;74(7):780–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28586827 2. Sailer A, Scholz SW, Nalls MA, Schulte C, Federoff M, Price TR, et al. A genome-wide association study in multiple system atrophy. Neurology [Internet]. 2016 Oct 11 [cited 2019 Feb 4];87(15):1591–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067544/pdf/NEUROLOGY2016719088.pdf 3. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet [Internet]. 2014 Sep [cited 2018 Sep 11];46(9):989–93. Available from: https://www.nature.com/articles/ng.3043.pdf

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-genome-wide-pleiotropic-approach-to-identify-the-genetic-architecture-of-multiple-system-atrophy-and-its-interaction-with-parkinsons-disease/