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 × 10^-6), "spending time in pub or social club" (r_g = 0.24, p = 2.77 × 10^-6), non-work related walking (r_g = - 0.25, p = 1.95 × 10^-6), college education (r_g = - 0.15, p = 7.08 × 10^-5), "ever diagnosed with panic attacks (r_g = 0.39, p = 4.24 × 10^-5), and "self-reported other gastritis including duodenitis" (r_g = 0.28, p = 1.4 × 10^-3). To assess the putative directionality of these genetic correlations, we conducted a latent causal variable analysis, identifying significant genetic causality proportions (gĉp) linking ALS genetic liability to seven traits. While the genetic component of "self-reported other gastritis including duodenitis" showed a causal effect on ALS (gĉp = 0.50, p = 1.26 × 10^-29), the genetic liability to ALS is potentially causal for multiple traits, also including an effect on "ever being diagnosed with panic attacks" (gĉp = 0.79, p = 5.011 × 10^-15) and inverse effects on "other leisure/social group activities" (gĉp = 0.66, p = 1 × 10^-4) and prospective memory result (gĉp = 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.