BRIDGING GENETIC DISCOVERY AND THERAPY: TRANSLATIONAL STUDIES TO FINE-MAPPING PTSD RISK AND MECHANISMS

Overall Abstract Posttraumatic stress disorder (PTSD) is a complex psychiatric condition shaped by genetic, epigenetic, and environmental factors. Despite rapid advances in genomic discovery, translating association signals into biological mechanisms and therapeutic strategies remains a central challenge. This symposium representing the Psychiatric Genomics Consortium PTSD (PGC-PTSD) working group will be chaired by Profs. Nikolaos Daskalakis (Boston University) and Caroline Nievergelt (UCSD), integrates statistical genetics, functional genomics, and translational neuroscience to advance our understanding of PTSD. The first presentation by Dr. Adam Maihofer (Assistant Professor @ UCSD) reports findings from the PGC-PTSD, including the largest GWAS of PTSD (> 3 million participants, > 500K cases) and the first well-powered rare variant association study (RVAS; > 700K participants). Over 300 genome-wide significant loci and 500 genes enriched for synaptic pathways were identified. Strikingly, the top RVAS genes—TET2, ASXL1, and DNMT3A—are epigenetic modifiers regulating DNA methylation, converging with GWAS findings to highlight gene–environment interactions in PTSD etiology. The second presentation by Dr. Nikolaos Daskalakis (Professor @ Boston University) examines gene–environment (GxE) interactions in postmortem human brain tissue (480 individuals, 10 brain regions), integrating transcriptomic, methylomic, proteomic, and single-cell data. Childhood trauma produced widespread molecular effects, with ∼7,740 significant GxE pairs across 1,477 genes enriched for synaptic protein homeostasis pathways. Approximately 25% of GxE effects were partially mediated through DNA methylation, with the central amygdala and medial prefrontal cortex emerging as key regions linking early adversity to PTSD and MDD risk. The third presentation by Dr. Liangying Yin (Post-doc @ Broad Institute) introduces MultiPred, an integrative transcriptomic imputation framework extending beyond traditional SNP-based models by incorporating DNA methylation and environmental variables. Its summary-statistics-based extension, S-MultiPred, requires only GWAS and EWAS summary data. Applied to PGC-PTSD data, it identifies novel PTSD-associated genes implicated in immune dysregulation and stress granule formation, undetectable by conventional transcriptome-wide association approaches. The fourth presentation by Dr. Olga Ponomareva (Instructor @ McLean Hospital/Harvard Medical School) functionally characterizes FOXP2, a top PTSD GWAS gene. Foxp2 knockdown in mouse amygdala intercalated neurons impairs fear acquisition and extinction, increases intrinsic excitability via reduced potassium channel conductance, and dysregulates fear-related gene networks including Wnt and corticotropin-releasing hormone signaling. Downstream targets are enriched for PTSD GWAS risk genes, corroborated in postmortem human amygdala, establishing FOXP2 as a transcriptional regulator of amygdala fear circuits and a promising therapeutic target. Together, these presentations address how genetic discoveries translate into causal biology, illuminate the roles of gene regulation and epigenetics in PTSD risk, and demonstrate how multi-omics integration and functional studies can inform precision medicine for PTSD. Discussion will be led by Dr. Kerry Ressler (McLean Hospital/Harvard Medical School).