{"doi":"10.1101/2022.09.27.22280414","title":"Phenome-wide genetic correlation analysis and genetically-informed causal inference of amyotrophic lateral sclerosis","abstract":"Abstract 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 ( 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 to seven traits. While the genetic component of “self-reported other gastritis including duodenitis” showed a positive 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 a positive 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 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.","journal":"medRxiv","year":2022,"id":311672,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8278,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":432396,"name":"Gita A. Pathak","orcid":"0000-0003-3943-0895","position":1,"is_corresponding":false},{"id":737637,"name":"Dóra Koller","orcid":"0000-0002-0415-0466","position":2,"is_corresponding":false},{"id":1008220,"name":"Danilo Porro","orcid":"0000-0001-5723-3700","position":3,"is_corresponding":false},{"id":1008221,"name":"Claudia Cava","orcid":"0000-0002-5540-4104","position":4,"is_corresponding":false},{"id":229994,"name":"Renato Polimanti","orcid":"0000-0003-0745-6046","position":5,"is_corresponding":false},{"id":584199,"name":"Salvatore D’Antona","orcid":"0000-0002-1283-8789","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:33:32.327694Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}