© 2014 . Background: Research on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort. Methods: Participants (. N=. 3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ). Results: The array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04×10-9), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5×10-6) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ. Conclusions: This first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.