Objective: The aim of this study to understand and define genetic overlap between multiple system atrophy (MSA) and autoimmune diseases such as Crohn’s disease (CD), Inflammatory bowel disease (IBD), Celiac disease (CeD), type-1 diabetes (T1D) and multiple sclerosis (MS).

Background: Emerging evidence highlighted the involvement of immune dysfunction in various neurodegenerative diseases including Alzheimer disease (AD), and Parkinson disease (PD). Previously published study using a genetic-pleiotropy approach showed considerable genetic overlap between PD and autoimmune diseases in particular T1D, and CD.

Method: We analyzed GWAS summary statistics for MSA (918 cases, 3864 controls) [1], CD (12194 cases, 34915 controls) [2], IBD (25042 cases, 34915 controls) [2], T1D (7514 cases, 9045 controls) [3], CeD (4533 cases, 10750 controls) [4] and MS (9772 cases, 17376 controls) [5] using conjunctional false discovery rate (conjFDR) [6], statistical framework to identify loci overlapping between MSA and autoimmune diseases. Conditional Q-Q plots were used to assess polygenic overlap between MSA and autoimmune diseases. The phenotype which showed significant genetic overlap were further evaluated to define disease relevant tissues and cell types. Functional mapping and genetic annotation of identified shared loci were done using FUMA.

Results: Conditional Q-Q plots suggest a substantial genetic overlap between MSA and CD/IBD (Figure1). We identified three linkage disequilibrium-independent loci shared (conjFDR<0.05) between MSA and CD, two of them were also shared between MSA and IBD (Table1, Figure2). Leading SNPs for two of these three loci are intergenic variants on chromosome 1 at 1q31.3 and chromosome 20 at 20p13, whereas the remaining one is in an intron of C7 gene at 5p13.1. None of these three loci were previously reported in the context of MSA, while two of them (1q31.3 and 5p13.1) reached genome-wide significance in the CD and IBD GWAS [2]. Furthermore, we identified a diverse range of tissues and cell types, which recapitulates disease pathogenesis. Finally, pathway analysis highlighted the involvement of several immune-related molecular processes (Figure3).

Conclusion: Our study identified a shared genetic component between MSA and IBD/CD, and thus providing further evidence regarding the involvement of gut dysfunction in MSA.

References: 1. Sailer, A., et al., A genome-wide association study in multiple system atrophy. Neurology, 2016. 87(15): p. 1591-1598. 2. de Lange, K.M., et al., Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet, 2017. 49(2): p. 256-261. 3. Barrett, J.C., et al., Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet, 2009. 41(6): p. 703-7. 4. Dubois, P.C., et al., Multiple common variants for celiac disease influencing immune gene expression. Nat Genet, 2010. 42(4): p. 295-302. 5. International Multiple Sclerosis Genetics, C., et al., Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 2011. 476(7359): p. 214-9. 6. Andreassen, O.A., et al., Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet, 2013. 9(4): p. e1003455.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-genome-wide-genetic-pleiotropy-approach-identified-shared-loci-between-multiple-system-atrophy-and-inflammatory-bowel-crohns-disease/