Somatically mutated genes in fatty liver disease have minimal influence on germline risk

Background Understanding the genetics of liver disease has the potential to facilitate clinical risk stratification. We recently identified six genes and one lncRNA enriched for acquired somatic mutations in patients with NAFLD and alcohol-related liver disease. We hypothesised that germline variation in these genes would be associated with risk of liver disease development and contribute to prognostication. Methods Genome-wide association study (GWAS) summary statistics were extracted from seven studies (>1.7 million participants) for variants near ACVR2A, ALB, CIDEB, FOXO1, GPAM, NEAT1 and TNRC6B for: aminotransferases, liver fat, HbA1c, diagnosis of NAFLD, ARLD, and cirrhosis. Findings were replicated using GWAS data from multiple independent cohorts. A phenome-wide association study was performed to examine for related metabolic traits, using both common and rare variants, including gene-burden testing. Results There was no evidence of association between rare germline variants or SNPs near five genes ( ACVR2A, ALB, CIDEB, FOXO1 , and TNRC6B ) and risk or severity of liver disease. Variants in GPAM were associated with liver fat (p=3.6×10 -13 ), ALT (p=2.8×10 -39 ), and serum lipid concentrations. Variants in NEAT1 demonstrated borderline significant associations with ALT (p=1.9×10 -11 ) and HbA1c, but not with liver fat, as well as influencing waist-to-hip ratio, adjusted for BMI. Conclusions Despite strong selective advantage to acquire somatic mutations at these loci, there was no evidence of an association between germline variation and markers of liver disease, except in GPAM . Polygenic risk scores based on germline variation alone will not capture prognostic data from genes affected by somatic mutations.