Phenome-wide genetic-correlation analysis and genetically informed causal inference of amyotrophic lateral sclerosis
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Published:2023-02-11
Issue:8
Volume:142
Page:1173-1183
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ISSN:0340-6717
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Container-title:Human Genetics
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language:en
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Short-container-title:Hum. Genet.
Author:
D’Antona Salvatore, Pathak Gita A., Koller Dora, Porro Danilo, Cava Claudia, Polimanti RenatoORCID
Abstract
AbstractLeveraging 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 (rg = − 0.21, p = 1.74 × 10–6), "spending time in pub or social club” (rg = 0.24, p = 2.77 × 10–6), non-work related walking (rg = − 0.25, p = 1.95 × 10–6), college education (rg = − 0.15, p = 7.08 × 10–5), “ever diagnosed with panic attacks (rg = 0.39, p = 4.24 × 10–5), and “self-reported other gastritis including duodenitis” (rg = 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.
Funder
National Institute on Drug Abuse National Institute on Deafness and Other Communication Disorders National Institute of Mental Health H2020 Marie Skłodowska-Curie Actions
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
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