POST-GWAS FOR PTSD: FROM RISK LOCI TO BIOLOGICAL MEANING

Posttraumatic stress disorder (PTSD) is a commonly occurring mental health consequence of exposure to extreme, often life-threatening events such as combat, sexual assault, natural disasters, and serious accidents. PTSD is frequently associated with other mental health disorders such as major depression and increased risk for suicide.

The Psychiatric Genomics Consortium PTSD (PGC-PTSD) workgroup has recently published the largest PTSD GWAS to date (Data Freeze 3), including over 90 different cohorts with over 1.25 million global participants and over 140,000 PTSD cases. With Data Freeze 3, PGC-PTSD has reached, for the first-time, adequate power to detect robust and replicable genomic signals for PTSD and has identified 95 PTSD loci across different ancestries.

Applying convergent multi-omic approaches, we tentatively identified potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators, developmental, axon guidance, and transcription factors, synaptic structure and function genes, and endocrine or immune regulators. Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology.

This symposium from leading members of our working group will summarize the most recent advances in PTSD genetics and present a variety of avenues to follow-up on PTSD risk loci, with the goal to increase our understanding of the biological bases of risk for PTSD, its delineation from co-morbid disorders such as MDD, and optimize transferability of results across diverse ancestries.

Dr. Adam Maihofer (University of California San Diego) will start off the symposium by presenting two complementary methods leveraging comorbidity information to refine PTSD associations and dissect genetic risk with the goal to detect risk genes specific to PTSD.

Dr. Nikolaos Daskalakis (Harvard Medical School/ McLean Hospital) will follow-up on GWAS top loci with multi-omic studies of postmortem brains of PTSD and MDD patients, showing that fine-mapping of PTSD and MDD genome-wide association study results reveals limited overlap between risk and disease processes at the gene and pathway level.

Alice Braun (PhD candidate, Charité – Universitätsmedizin Berlin) will explore the immunogenetic basis of PTSD by focusing on the major histocompatibility complex (MHC), a complex region on chromosome 6 that harbors numerous genetic variants such as human leukocyte antigen (HLA) alleles that are crucial for immune function and has been identified as a risk locus for PTSD.

Finally, Dr. Marcos Santoro (Universidade Federal de São Paulo) will describe our efforts in the PGC-PSTD Ancestry Working Group on improving the inclusion of admixed individuals in PGC-PTSD, which currently include more than 50,000 African American and 13,000 Latin American individuals, with different and complex patterns of admixture according to the region they have been collected from. The talk will conclude with a presentation of our user-friendly pipeline for local ancestry inference (LAI).

After these 4 presentations, Dr. Joel Gelernter (Yale University School of Medicine) will lead the discussion, summarize and integrate the findings with a focus on the next steps for the consortium as we move from discovery of PTSD risk loci to biological meaning and dissection of the pathogenesis of trauma- and stress-related disorders.