Abstract
BackgroundEpidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture.MethodsTo examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn’s disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method.ResultsWe identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification.ConclusionsOur findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
Highlights
Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders
genome-wide association studies (GWAS) summary statistics We investigated the genetic links between ALS [17] and 10 autoimmune disorders including asthma [18], multiple sclerosis (MS) [19], psoriasis [20], rheumatoid arthritis (RA) [21], systemic lupus erythematosus (SLE) [22], type 1 diabetes (T1D) [23], celiac disease (CeD) [24], inflammatory bowel disease (IBD) [25], Crohn’s disease (CD) [25], and ulcerative colitis (UC) [25] based on GWAS summary statistics
Genetic correlation We identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD (Additional file 1: Table S2)
Summary
Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. Epidemiologic studies presented that several pre-existing autoimmune disorders are associated with an increased risk of ALS [11]. Intermediate alleles of C9orf, the most common genetic cause of ALS, were suggested to be associated with systemic autoimmune diseases, indicating the role of C9orf in immunity regulation [12]. Mice harboring loss-of-function mutations in the ortholog of C9orf cause fatal autoimmune diseases [13] These associations raise the possibility of shared genetic or environmental risk factors, or clues to modifiable triggers that might thereby affect ALS incidence. A systematic study is necessary to decipher whether shared polygenic risk variants exist between ALS and autoimmune diseases, and whether specific molecular biological pathways are involved
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