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Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.

ABSTRACT: Epidemiologic studies recognize that trauma and posttraumatic stress are associated with heightened suicidal behavior severity, yet examination of these associations from a genetic perspective is limited. 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 five suicidality risk loci, including the male-associated rs2367967 (CWC22), which replicated in an independent cohort. All GEWIS-significant loci exhibited interaction effects where at least 5% of the sample had environmental profiles conferring opposite SNP effects from the majority. We identified PTSD as a primary driving environment for GxE at suicidality risk loci. The male suicidality GEWIS was enriched for three middle-temporal-gyrus inhibitory neuron transcriptomic profiles: SCUBE- and PVALB-expressing cells (? = 0.028, p = 3.74 × 10^-4), OPRM1-expressing cells (? = 0.030, p = 0.001), and SPAG17-expressing cells (? = 0.029, p = 9.80 × 10^-4). Combined with gene-based analyses (CNTN5 p _association = 2.38 × 10^-9, p _interaction = 1.51 × 10^-3; PSMD14 p _association = 2.04 × 10^-7, p _interaction = 7.76 × 10^-6; HEPACAM p _association = 2.43 × 10^-6, p _interaction = 3.82 × 10^-7) including information about brain chromatin interaction profiles (UBE2E3 in male neuron p = 1.07 × 10^-5), our GEWIS points to extracellular matrix biology and synaptic plasticity as biological interactors with the effects of potentially modifiable lifetime traumatic experiences on genetic risk for suicidality. Characterization of molecular basis for the effects of traumatic experience and posttraumatic stress on risk of suicidal behaviors may help to identify novel targets for which more effective treatments can be developed for use in high-risk populations.

SUBMITTER: Wendt FR

PROVIDER: S-EPMC7905234 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.

Wendt Frank R FR Pathak Gita A GA Levey Daniel F DF Nuñez Yaira Z YZ Overstreet Cassie C Tyrrell Chelsea C Adhikari Keyrun K De Angelis Flavio F Tylee Daniel S DS Goswami Aranyak A Krystal John H JH Abdallah Chadi G CG Stein Murray B MB Kranzler Henry R HR Gelernter Joel J Polimanti Renato R

Neurobiology of stress 20210218

Epidemiologic studies recognize that trauma and posttraumatic stress are associated with heightened suicidal behavior severity, yet examination of these associations from a genetic perspective is limited. 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 five sui ...[more]

PMID: 33665242

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Dataset Information

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.

Publications

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.

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