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Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Abstract

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

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Fig. 1: Data sources and analyses in PTSD Freeze 3.
Fig. 2: GWAS meta-analyses in European and multi-ancestry individuals identify a total of 95 PTSD risk loci.
Fig. 3: Manhattan plots of PTSD associations in multi-omic analyses.
Fig. 4: Gene prioritization in PTSD loci.
Fig. 5: PRS analysis for PTSD across different datasets and ancestries.

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Data availability

Summary statistics for PGC-PTSD Freeze 3 will be made available upon publication under the accession ID ptsd2024 via the PGC website (https://pgc.unc.edu/for-researchers/download-results/). Access to study-level summary statistics and genotype data can be applied by using the PGC data access portal (https://pgc.unc.edu/for-researchers/data-access-committee/data-access-portal/).

Code availability

Analysis code is made available at GitHub (https://github.com/nievergeltlab/freeze3_gwas) and Zenodo (https://doi.org/10.5281/zenodo.10182702)118.

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Acknowledgements

Major financial support for the PTSD-PGC was provided by the National Institute of Mental Health (NIMH; R01MH106595 (to K.C.K., C.M.N., K.J.R. and M.B.S.), R01MH124847 (to C.M.N.) and R01MH124851 (to A.D.B., L.K.D. and K.C.K.)), the Stanley Center for Psychiatric Research at the Broad Institute and Cohen Veterans Bioscience. Statistical analyses were carried out on the NL Genetic Cluster computer (URL) hosted by SURFsara. Genotyping of samples was supported in part through the Stanley Center for Psychiatric Genetics at the Broad Institute of MIT and Harvard. This research has been conducted using the UKB resource under application 41209. This work would not have been possible without the contributions of the investigators who comprise the PGC-PTSD working group, and especially the more than 1,307,247 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank A.E. Aiello, B. Bradley, A. Gautam, R. Hammamieh, M. Jett, M.J. Lyons, D. Maurer, M.R. Mavissakalian and the late C.R. Erbes and R.E. McGlinchey for their contributions to this study.

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