Analysis of whole-exome data of nonobese NAFLD patients from India reveals association with new markers on functionally relevant genes and pathways.

Nonalcoholic fatty liver disease (NAFLD) occurs in a significant number of nonobese individuals, especially in Asian populations. Many genetic loci are associated with NAFLD. However, no exome-wide analysis of polymorphism data to identify asso- ciations with NAFLD is available for nonobese individuals from Asia. We have sought to fill this gap. With informed consent, we selected individuals from a defined population in India and assessed their liver fat-graded per international recommendations, and their demo- graphic and anthropometric data were collected. A set of 153 individuals were identified with high-grade liver fat. For each of these fatty- liver individuals (cases), two controls of the same sex with no or little liver fat were selected, the age and BMI of each control not exceeding 5 years and 5 kg/m², respectively, of the case. Whole-genome sequencing was done for each individual. For association analysis, we selected only nonsynonymous germline single-nucleotide polymorphisms (SNPs) in coding regions located on genes expressed in the liver. We removed SNPs and individuals with compromised quality and informativeness. We carried out association analysis in this high-quality data set and validated the results using a novel bootstrap procedure. On the basis of this high-stringency association analysis using exome- wideSNP data on 438 cases and controls, we identified 30 significant SNPs on 24 genes. Of these, 21 SNPs from 17 genes are hitherto unreported. We have determined that most of the significant SNPs are functionally relevant. Pathway analysis revealed that the genes on which these SNPs are located are involved in liver dysfunction.