Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E

Background & Aims Genome-wide association studies (GWAS) have identified several risk loci for non-alcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. Approach & Results We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for BMI and adjusting for alcohol intake. 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components and genotyping batch. We performed a GWA meta-analysis using available summary association statistics from two previously published case-control GWAS of NAFLD. Six risk loci were identified (P<5*10^(−8)) of which one is novel in GWAS (rs429358 in APOE) and five are known (PNPLA3, TM6SF2, GCKR, MARC1 and TRIB1). Rs429358 (P=2.17*10^(−11)) is a missense variant within the APOE gene determining ⍰4 vs ⍰2/⍰3 alleles. All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals) with others demonstrating consistent direction and magnitude of effect. All 6 loci were significant on meta-analysis including APOE P=3.42*10^(−13) with consistent direction and magnitude of effect in all 6 loci in all three studies. The ⍰4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95%CI 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusions This GWAS demonstrates that the ∈ 4 allele of APOE is strongly associated with protection against NAFLD.