Yuan, QiaopingHodgkinson, ColinLiu, XiaochenBarton, Bruce ADiazgranados, NancySchwandt, MelanieMorgan, TimothyBataller, RamonLiangpunsakul, SuthatNagy, Laura EGoldman, David2024-08-292024-08-292024-07-26Yuan Q, Hodgkinson C, Liu X, Barton B, Diazgranados N, Schwandt M, Morgan T, Bataller R, Liangpunsakul S, Nagy LE, Goldman D; with DASH, InTEAM, SCAHC, TREAT and Alcohol Hepatitis Genomics consortia. Exome-wide association analysis identifies novel risk loci for alcohol-associated hepatitis. Hepatology. 2024 Jul 26. doi: 10.1097/HEP.0000000000001027. Epub ahead of print. PMID: 39058584.1527-335010.1097/HEP.000000000000102739058584https://hdl.handle.net/20.500.14038/53731Background and aims: Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder (AUD). Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variation that contribute to the development of AH. Approach and results: Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified exome-wide significant association for AH at PNPLA3, as previously observed for AC in GWAS, although with a much lower effect-size. SNPs of large effect-size at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX4 was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B. Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation. Conclusions: This study has identified two new genes of high effect size with a previously unknown contribution to ALD, and highlights both the overlap in etiology between liver diseases, and the unique origins of AH.enIn the public domain. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.alcohol-associated hepatitisinflammationalcohol-associated liver diseasewhole exome sequencingAccepted ManuscriptHepatology (Baltimore, Md.)