Methylome profile of World Trade Center related PTSD

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ABSTRACT The 9/11 World Trade Center terrorist attack was a massive disaster, resulting in long-term psychological trauma to the responders, with 17% of responders experiencing symptoms consistent with PTSD more than two decades later. DNA methylation, the most widely studied epigenetic mark can illuminate gene-environment interaction and provide biological insights into the etiology and maintenance of PTSD. Although a number of epigenome- wide association studies (EWAS) have been conducted to identify CpGs associated with PTSD, many of these studies are underpowered. Ongoing efforts to address small sample sizes of individual cohort include establishing the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, which is the largest epigenetic consortium to date. Large sample EWAS in peripheral blood are feasible and have the potential to identify accessible biomarker for PTSD, however these studies also highlight the need for more data and stronger designs. Specifically, the limitations of PGC include large methodological heterogeneity of the participating study cohorts. The proposed study builds on existing studies by using more powerful design that will produce novel findings, and at the same time allow new data to be combined with PGC data to further increase power and ensure generalizability of the results. To this end, genome-wide methylation profiling with the Illumina Infinium MethylationEPIC BeadChip arrays will be generated using biobanked blood samples on a subset of n=1,850 responders who have been genotyped. In Aim 1, EWAS will be performed to identify CpGs associated with PTSD and PTSD dimensions. In Aim 2, genetic variants associated with methylation will be derived via methylation quantitative trait loci analysis and integrated with PTSD genetic risk variants to identify putatively causal CpGs and variants for PTSD. In Aim 3, results from the proposed study will be combined with the PGC results to maximize power to detect generalizable findings. To enhance the impact of this study, an exploratory aim is included to identify methylation subclasses associated with PTSD and health outcomes. This will be the largest single-cohort PTSD study and is powered to identify novel epigenetic mechanisms that maintain symptoms in chronic PTSD. This research will help to explicate pathophysiology of this disorders on molecular level, which may become targets for treatment development.