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Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide and may progress to nonalcoholic steatohepatitis (NASH). Although emerging evidence suggests that NASH would be an important driver of hepatocellular carcinoma (HCC), molecularly what drives the transition of NAFLD to NASH and then HCC has not been clearly defined. Since NASH is a mitochondrial disease, we aimed to determine genetic variants associated with mitochondrial dysfunction linked to NASH and NASH-related HCC. We performed an integrative genomics analysis by analyzing a large-scale genome-wide association study of the body fat distribution-related variants in 344,369 individuals from multiple ancestries. And we linked these results to the top 24 significant variants to NASH and NASH-related HCC in 1,009 individuals from the NCI-UMD cohort. We also performed the expression quantitative trait loci (eQTL) analysis on candidate variants. We analyzed the 3D genome architecture especially chromatin topology based on UCSC Genome Browser that influences the expression of candidate variants. As a result, we identified rs3747579-TT, an eQTL to a mitochondrial chaperone Hsp40, also known as DNAJA3 rather than a coding variant, as a risk allele linked to NASH-related HCC. HCC patients with rs3747579-TT variant had a poor prognosis compared to HCC patients with rs3747579-CT or CC variant. We confirmed that HCC with rs3747579-TT had a reduced expression of DNAJA3, encoding a protein that maintains mitochondrial homeostasis. Consistently, HCC patients with low DNAJA3 expression had a poor prognosis. We found a specific site based on chromatin topology that may influence rs3747579 to regulate the expression of DNAJA3. In summary, we identified rs3747579-TT as a functional polymorphic variant of DNAJA3 that may be responsible for the development of NASH and NASH-related HCC. Citation Format: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang. A functional genetic polymorphism of mitochondrion-associated DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1404.