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Trauma and posttraumatic stress interact with sex-specific risk loci for suicidality and converge on brain extracellular matrix biology and synaptic plasticity

By Frank R Wendt, Gita A Pathak, Daniel F Levey, Yaira Z. Nunez, Cassie Overstreet, Chelsea Tyrrell, Keyrun Adhikari, Flavio De Angelis, Daniel S. Tylee, Aranyal Goswami, John H Krystal, Chadi Abdallah, Murray B Stein, Henry R. Kranzler, Joel Gelernter, Renato Polimanti

Posted 21 May 2020
medRxiv DOI: 10.1101/2020.05.18.20105734

We performed a multivariate gene-by-environment genome-wide interaction study (GEWIS) of suicidality in 123,633 individuals using a covariance matrix based on 26 environments related to traumatic experiences, posttraumatic stress, social support, and socioeconomic status. We discovered sex-specific risk loci exhibiting interaction effects driven by PTSD, including the male-specific rs2367967 (CWC22), which replicated in an independent cohort. Sex-specific cell-type transcriptome enrichment, gene-based analyses, and locus annotation point to extracellular matrix biology and synaptic plasticity as biological mediators of the effects of lifetime traumatic experiences on genetic risk for suicidality.

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