Common and rare genomic risk factors for PTSD with implications for autoimmune disorders and inflammatory biomarkers

Background: Posttraumatic stress disorder (PTSD) is a potential consequence of exposure to traumatic stress. PTSD has severe psychological, physical, interpersonal, and societal costs. The development of PTSD following traumatic stress is heritable. Studies of genetic risk factors have focused on common single nucleotide polymorphisms. The overwhelming majority of risk PTSD loci have yet to be identified. The integration of detailed PTSD phenotyping has shown promise to increase power to identify PTSD risk loci. Rare genetic variation has only been sparsely examined in the context of PTSD, yet evidence is emerging that rare variation such as copy number variation (CNV) is relevant to psychiatric disorders. Findings of large genetic studies of PTSD and co-morbid disorders make it possible to make causal inferences and provide mechanistic insights using Mendelian Randomization (MR).Methods: This dissertation includes three studies, all of which were conducted among participants from the Psychiatric Genomics Consortium-PTSD data collection, a consortia made to investigate genomic risk factors for PTSD through meta-analysis of PTSD cohorts. Study 1 was a GWAS of PTSD symptom scores and lifetime trauma exposure phenotypes to identify common genetic risk variation for PTSD. Study 2 was an investigation of rare CNV and PTSD. Study 3 leverages GWAS summary statistics from PTSD and inflammatory phenotypes related to PTSD, using MR to make causal inferences about PTSD and inflammatory diseases. Results: In study one, multiple genetic risk loci were identified for PTSD and for lifetime trauma exposure, with the two traits having a substantial degree of genetic overlap. In study two, PTSD risk was elevated in CNVs that crossed over known neurodevelopmental CNV regions and pathways related to the function of the nervous system and brain. In study three, PTSD had evidence of causal effect on asthma and psoriasis, as well as inflammatory biomarkers.Conclusion: This dissertation enhances the general field of PTSD genetics, having identified novel common and rare risk variation, and supports hypotheses that PTSD has a causal relationship with certain comorbid diseases with an inflammatory component