Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors.

Tae‐Hwi Schwantes‐An ,David Goldman ,Jean‐Marc Jacquet ,Florian Eyer ,Romain Moirand ,Christopher P Day ,Sebastian Mueller ,Munir Pirmohamed ,Pascal Perney ,Pierre Nahon ,Steven Masson ,Tatiana Foroud ,Ann K Daly ,Dermot Gleeson ,John B Whitfield ,Heather J Cordell ,Andrew Thompson ,Philippe Maury ,Rebecca Darlay ,Paul S Haber ,Felix Stickel ,Guruprasad P Aithal ,Greg Botwin ,Beat Muellhaupt ,Timothy R Morgan ,Suthat Liangpunsakul ,Sylvie Naveau ,Helmut K Seitz ,Tiebing Liang ,Bertrand Nalpas ,Lawrence Lumeng ,Michael Soyka ,Devanshi Seth

doi:10.1002/hep.31535

Abstract

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. 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. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Highlights

ObjectivesThe aim of this study was to identify common genetic variants that underlie risk for alcohol-related cirrhosis (ALC)
Laboratory of Neurogenetics (LNG) cohort Genotype and phenotype data from 860 heavy-drinking subjects who had given consent as part of two NIH screening/natural history protocols (98-AA-009; 05-AA-0121) were provided by the Laboratory for Neurogenetics (LNG) at the National Institutes on Alcohol Abuse and Alcoholism (NIAAA, Rockville, MD, USA) as additional heavy drinking controls
PRIMARY Genome-wide association study (GWAS) ANALYSIS The primary GenomALC GWAS analysis identified two genome-wide significant associations (Figure 1, Supplementary Figure S1). rs738409 on chromosome 22, located in PNPLA3, was significantly associated with increased risk of alcohol-related cirrhosis (ALC), with a p-value of 4.93x10-17 and an Odds Ratio (OR) of 2.19 (95% confidence interval (CI), 1.81 - 2.54) for each copy of the G allele. rs4607179 on chr4, located near HSD17B13, was associated with lower risk of ALC with a p-value of 1.09x1010 and OR of 0.57 for each copy of the C allele (Table 1)