Non-alcoholic fatty liver(NAFLD) is prevalent in Asians despite the low obesity rate. We hypothesized that the haplotype of genetic variants in the 22q13 loci has a strong association with non-alcoholic fatty liver disease (NAFLD) that can be identified by genome-wide association study and that lifestyles may interact with the haplotype. We tested the hypothesis in middle-aged and elderly adults in a large city hospital-based cohort from the KoGES study. Men and women diagnosed with fatty liver, but who respectively consumed over 40 and 30 g ethanol per day were excluded. The haplotype of the selected SNPs from the 22q13 loci that influences NAFLD risk was generated. Among the 27374 participants, 1486 (5.4%) were diagnosed with NAFLD. LARGE_rs240072, RBFOX2_rs11089778, TRIOBP_rs12628603, PNPLA3_rs738409, and PARVB_rs2073080 in the 22q13 loci were included in the haplotype. Participants with the minor haplotype had 1.8, 2.3, and 1.8 times higher in the risk for NAFLD and serum AST and ALT activities, respectively, than those with the major haplotype. BMI, waist circumferences, serum glucose concentrations, and blood pressure interacted with the haplotype for NAFLD risk. We also found that a high carbohydrate intake and a dietary pattern characterized by high noodle and meat consumption significantly interacted with the minor haplotype to increase the risk of NAFLD. We hypothesized that the high incidence of NAFLD among Koreans, despite a relatively low incidence of obesity, might be due to genetic factors and perhaps their interactions with dietary patterns. The hypothesis was accepted since this study confirmed that participants with the minor allele of the haplotype in the 22q13 loci had a higher NAFLD risk that was exacerbated by high intakes of carbohydrates and a dietary pattern characterized by high noodle and meat consumption.Copyright © 2020 Elsevier Inc. All rights reserved.