Abstract
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.
Highlights
Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and obesity-related traits
Robust genetic enrichment was observed for ALS conditional on body mass index (BMI), body fat percentage (BFP), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and type 2 diabetes (T2D), but minimal enrichment on the other traits. 9 shared genetic loci with conjunctional false discovery rate (FDR) < 0.05 was identified, among which 6 were replicated in a second ALS cohort, including rs3849942 (C9orf72), rs170663 (G2E3), rs8018993 (SCFD1), rs978220 (ATXN3), rs62333164 (CLCN3) and rs12603276 (GGNBP2)
We systematically evaluated shared genetic risk between ALS and eleven obesity-related traits, including obesity traits like BMI, waist hip ratio (WHR), body fat percentage (BFP) and birth weight (BW), obesity-related lipid traits like LDL-C, HDL-C, total cholesterol (TC) and TG, and obesity related glucose traits like T2D, fasting glucose (FG) and fasting insulin (FI)
Summary
Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and obesity-related traits. Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disorder with an average survival period around 3–5 years since the symptom onset, which brings a substantial impact on the quality of life for patients and their families, and huge socioeconomic burdens[1, 2]. With the advent of next-generation sequencing, emerging evidence suggests a substantial genetic component underlying ALS[3, 4]. Large genome-wide association studies (GWAS) have identified a growing number of susceptibility loci related to ALS and provided novel insight into the pathogenesis of ALS[5, 6]. Due to the polygenic architecture of ALS, risk loci with weak associations cannot be identified with current GWAS sample size[7]. Some of the nominated risk loci have not been implicated in disease pathogenesis and are awaiting further exploration
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