Phenome-wide genetic-correlation analysis and genetically informed causal inference of amyotrophic lateral sclerosis

Leveraging genome-wide association statistics generated from a large study of amyotrophic lateral sclerosis (ALS; 29,612 cases and 122,656 controls) and UK Biobank (UKB; 4,024 phenotypes, up to 361,194 participants), we conducted a phenome-wide analysis of ALS genetic liability and identified 46 genetically correlated traits, such as fluid intelligence score (r(g) = - 0.21, p = 1.74 x 10(-6)), "spending time in pub or social club" (r(g) = 0.24, p = 2.77 x 10(-6)), non-work related walking (r(g) = - 0.25, p = 1.95 x 10(-6)), college education (r(g) = - 0.15, p = 7.08 x 10(-5)), "ever diagnosed with panic attacks (r(g) = 0.39, p = 4.24 x 10(-5)), and "self-reported other gastritis including duodenitis" (r(g) = 0.28, p = 1.4 x 10(-3)). To assess the putative directionality of these genetic correlations, we conducted a latent causal variable analysis, identifying significant genetic causality proportions (gcp) linking ALS genetic liability to seven traits. While the genetic component of "self-reported other gastritis including duodenitis" showed a causal effect on ALS (gcp = 0.50, p = 1.26 x 10(-29)), the genetic liability to ALS is potentially causal for multiple traits, also including an effect on "ever being diagnosed with panic attacks" (gcp = 0.79, p = 5.011 x 10(-15)) and inverse effects on "other leisure/social group activities" (gcp = 0.66, p = 1 x 10(-4)) and prospective memory result (gcp = 0.35, p = 0.005). Our subsequent Mendelian randomization analysis indicated that some of these associations may be due to bidirectional effects. In conclusion, this phenome-wide investigation of ALS polygenic architecture highlights the widespread pleiotropy linking this disorder with several health domains.