Shared genetic links between amyotrophic lateral sclerosis and obesity-related traits: a genome-wide association...

Epidemiological and clinical studies have suggested comorbidities between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture. To examine whether genetic enrichment exists between ALS and obesity-related traits and to identify shared risk loci, we analyzed summary statistics from genome-wide association studies using the conditional false discovery rate statistical framework, and further conducted functional enrichment analysis. Robust genetic enrichment was observed for ALS conditional on body mass index, body fat percentage, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and type 2 diabetes. Nine shared genetic loci were identified, among which 6 were replicated in a second ALS cohort, including C9orf72, G2E3, SCFD1, ATXN3, CLCN3 and GGNBP2. We further identified GGNBP2 as a novel ALS risk gene, by integrating summary data-based Mendelian randomization analysis. Functional enrichment analysis indicated that the shared risk genes were involved in 2 pathways, namely membrane trafficking and vesicle-mediated transport. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.