Abstract DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair is involved in cancer. We hypothesize that genetic variants in DNA repair genes are associated with risk of lung cancer. To test this hypothesis, we performed a large-scale meta-analysis of 123,371 SNPs in 169 DNA repair genes obtained from six datasets of previously published genome-wide association studies (GWASs), consisting of 12,160 lung cancer cases and 16,838 controls. We evaluated functional relevance of the identified, previously unpublished important and significant SNPs. Across the six GWASs, 14 SNPs were found to be significantly associated with lung cancer risk with a false discovery rate (FDR) of P < 0.05, of which rs114596632 in GTF2H4 at 6q31.33 was the most statistically significant SNP (OR = 1.19, 95% CI = 1.12-1.25, Pcombined = 5.40 × 10−10). The SNP rs114596632 was not strongly correlated with the previously reported GWAS hit MSH5 rs3131379 in that region (r2 = 0.383). Further mapping of the human leukocyte antigen (HLA) region identified that rs114596632 was partially tagged by HLA-B*0801 (r2 = 0.592) and HLA-C*0701 (r2 = 0.675). Importantly, the rs114596632 T allele was significantly associated with decreased DNA repair capacity (DRC) measured in peripheral T lymphocytes and decreased mRNA expression levels of GTF2H4 in lymphoblastoid cell lines. We also validated two previously known SNPs in DNA repair genes MSH5 and XRCC4 associated with lung cancer risk. Subsequent pathway analysis with gene relationships across implicated loci (GRAIL) revealed multiple significant connections for GTF2H4, ERCC2, and MMS19. Our results provide evidence that genetic variants of GTF2H4 confer susceptibility to lung cancer and suggest the involvement of GTF2H4 in the etiology of lung cancer. (Supported by U19CA148127, R01CA CA074386, R01CA092824 and the start-up funds from Duke Cancer Institute, Duke University Medical Center) Citation Format: Qingyi Wei, Hongliang Liu, Zhensheng Liu, Christopher I. Amos, Jennifer A. Doherty, Heike Bickeboller, Rayjean J. Hung, Paul Brennan, Richard Houlston, Maria Teresa Landi, Neil E. Caporaso, David Christiani. A novel variant in DNA repair gene GTF2H4 is associated with lung cancer risk: A reanalysis of GWAS datasets from the TRICL consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4597. doi:10.1158/1538-7445.AM2015-4597