GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10 − 20). This effect was consistent in both pediatric (p = 9.92 × 10 − 6) and adult (p = 9.73 × 10 − 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10 − 8 , beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10 − 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10 − 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10 − 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.

Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

“…13,14 To date, most adequately powered GWASs relevant to NAFLD have addressed either radiologically determined HTGC 4,6,12 or clinical biochemistry parameters such as ALT. 12,15 They have therefore been unable to address the more clinically relevant phenotypes of steatohepatitis grade or fibrosis stage (reviewed 3 ). One GWAS has assessed a large number of histologically characterised patients, reporting associations with both PNPLA3 and with chromosome 19 close to TM6SF2.…”

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

“…The same TRIB1 region was identified in a recent GWAS of NAFLD, lending further credibility to the relevance of this locus. 53 As well as providing insight into the pathobiology of alcohol-related cirrhosis, a deeper understanding of the underlying genetics could, in time, help clinicians differentiate the minority of liver disease patients at high risk of serious liver morbidity from the low-risk majority. In principle therefore, host genetic data may help to increase earlier detection of chronic liver disease in high-risk patients-thus addressing the issue of frequently delayed diagnosis of chronic liver disease.…”

Noncoding RNAs in Nonalcoholic Fatty Liver Disease: Potential Diagnosis and Prognosis Biomarkers

“…As said above, NAFLD implicates intricate interactions between many risk factors and genetic predisposition [ 19 ]. Several studies have suggested a genetic underpinning for NAFLD [ 20 , 21 ].…”