{"doi":"10.1101/2020.12.26.20248491","title":"A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation","abstract":"Abstract Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance – including 25 without prior NAFLD or ALT associations – with one additional locus identified in European-American-only and two in African-American-only analyses (P<5×10 -8 ). External replication in cohorts with NAFLD defined by histology (7,397 cases, 56,785 controls) or liver fat extracted from radiologic imaging (n=44,289) validated 17 SNPs (P<6.5×10 -4 ) of which 9 were novel ( TRIB1 , PPARG , MTTP , SERPINA1 , FTO , IL1RN , COBLL1 , APOH , and IFI30 ). Pleiotropy analysis showed that 61 of 77 trans-ancestry and all 17 validated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.","journal":"medRxiv","year":2021,"id":213718,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7058,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":57626,"name":"Shweta Ramdas","orcid":"0000-0001-8888-4661","position":1,"is_corresponding":false},{"id":805856,"name":"Kimberly Lorenz","orcid":"0000-0001-8674-2942","position":2,"is_corresponding":false},{"id":24754,"name":"Xiuqing Guo","orcid":"0000-0002-5264-5068","position":3,"is_corresponding":false},{"id":625123,"name":"Rebecca Darlay","orcid":"0000-0002-7526-5527","position":4,"is_corresponding":false},{"id":97259,"name":"Heather J. 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