TY - JOUR
T1 - Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors
AU - for the GenomALC Consortium
AU - Schwantes-An, Tae Hwi
AU - Darlay, Rebecca
AU - Mathurin, Philippe
AU - Masson, Steven
AU - Liangpunsakul, Suthat
AU - Mueller, Sebastian
AU - Aithal, Guruprasad P.
AU - Eyer, Florian
AU - Gleeson, Dermot
AU - Thompson, Andrew
AU - Muellhaupt, Beat
AU - Stickel, Felix
AU - Soyka, Michael
AU - Goldman, David
AU - Liang, Tiebing
AU - Lumeng, Lawrence
AU - Pirmohamed, Munir
AU - Nalpas, Bertrand
AU - Jacquet, Jean Marc
AU - Moirand, Romain
AU - Nahon, Pierre
AU - Naveau, Sylvie
AU - Perney, Pascal
AU - Botwin, Greg
AU - Haber, Paul S.
AU - Seitz, Helmut K.
AU - Day, Christopher P.
AU - Foroud, Tatiana M.
AU - Daly, Ann K.
AU - Cordell, Heather J.
AU - Whitfield, John B.
AU - Morgan, Timothy R.
AU - Seth, Devanshi
N1 - Publisher Copyright:
© 2020 by the American Association for the Study of Liver Diseases.
PY - 2021/5
Y1 - 2021/5
N2 - Background and Aims: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and Results: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10−17) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10−10) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10−8) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
AB - Background and Aims: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and Results: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10−17) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10−10) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10−8) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
UR - http://www.scopus.com/inward/record.url?scp=85099307095&partnerID=8YFLogxK
U2 - 10.1002/hep.31535
DO - 10.1002/hep.31535
M3 - Article
C2 - 32853455
AN - SCOPUS:85099307095
SN - 0270-9139
VL - 73
SP - 1920
EP - 1931
JO - Hepatology
JF - Hepatology
IS - 5
ER -
