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 genetic correlation analysis of ALS and identified 46 genetically-correlated traits, such as fluid intelligence score (rg = -0.21, p = 1.74x10-6), 'spending time in pub or social club' (rg = 0.24, p = 2.77x10-6), non-work related walking (rg = -0.25, p = 1.95x10-6), college education (rg = -0.15, p = 7.08x10-5), 'ever diagnosed with panic attacks' (rg = 0.39, p = 4.24x10-5), and 'self-reported other gastritis including duodenitis' (rg = 0.28, p = 1.4x10-3). To assess the putative directionality of these genetic correlations, we conducted a latent causal variable analysis, identifying significant genetic causality proportions (gcp) linking ALS to seven traits. While the genetic component of 'self-reported other gastritis including duodenitis' showed a positive causal effect on ALS (gcp = 0.50, p = 1.26x10-29), the genetic liability to ALS is potentially causal for multiple traits, also including a positive effect on 'ever being diagnosed with panic attacks' (gcp = 0.79, p = 5.011x10-15) and inverse effects on 'other leisure/social group activities' (gcp = 0.66, p = 1x10-4) 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 bi-directional effects. In conclusion, this is the first phenome-wide investigation of ALS polygenic architecture, highlighting the complex pleiotropy linking this disorder with different health domains.

Dr. Polimanti is paid for his editorial work on the journal Complex Psychiatry and received a research grant from Alkermes. The other authors reported no biomedical financial interests or potential conflicts of interest.

The authors would like to thank for the financial support: 'INnovazione, nuovi modelli TEcnologici e Reti per curare la SLA' (INTERSLA) (ID 1157625) - Call HUB ricerca e Innovazione, promoted by Lombardy Region. The project was co-funded from the 2014-2020 POR FESR resources. IBFM-CNR thanks the support received by the Italian CNR through the Short-Term Mobility program 2021. In addition, CNR investigators acknowledge the National Recovery and Resilience Plan- National Biodiversity Future Center (NBFC)- ID: CN0000033. Yale investigators acknowledge grants from the National Institutes of Health (RF1 MH132337, R33 DA047527, R21 DC018098, and T32 MH014276), One Mind, and the European Commission (H2020 Marie Sklodowska-Curie Individual Fellowship 101028810).

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This study was conducted using genome-wide association statistics generated by previous studies. Owing to the use of previously collected, deidentified, aggregated data, this study is exempt from institutional review board approval.

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