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

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

doi:10.1016/j.ynstr.2021.100309

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

Neurobiol Stress. 2021 Feb 18:14:100309. doi: 10.1016/j.ynstr.2021.100309. eCollection 2021 May.

Authors

Frank R Wendt^{1

2}, Gita A Pathak^{1

2}, Daniel F Levey^{1

2}, Yaira Z Nuñez^{1

2}, Cassie Overstreet^{1

2

3}, Chelsea Tyrrell^{1

2}, Keyrun Adhikari^{1

2}, Flavio De Angelis^{1

2}, Daniel S Tylee^{1

2}, Aranyak Goswami^{1

2}, John H Krystal¹, Chadi G Abdallah^{1

2}, Murray B Stein^{4

5}, Henry R Kranzler^{6

7}, Joel Gelernter^{1

2

8}, Renato Polimanti^{1

2}

Affiliations

¹ Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06510, USA.
² VA CT Healthcare System, West Haven, CT, 06520, USA.
³ National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven CT, 06520, USA.
⁴ Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA.
⁵ Departments of Psychiatry and Family Medicine & Public Health, University of California San Diego, La Jolla, CA, USA.
⁶ University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
⁷ Crescenz Veterans Affairs Medical Center, Philadelphia, PA, 19104, USA.
⁸ Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA.

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 (β = 0.028, p = 3.74 × 10^-4), OPRM1-expressing cells (β = 0.030, p = 0.001), and SPAG17-expressing cells (β = 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.

Keywords: BF, Bayes factor; ECM, Extracellular matrix; EE, Environmental enrichment; FUMA, Functional Mapping and Annotation of Genome-Wide Association Studies; GEWIS, gene-by-environment genome-wide interaction study; Gene-by-environment; MAGMA, Multi-marker Analysis of GenoMic Annotation; MICE, Multivariate Imputation via Chained Equations; Posttraumatic stress; Social support; Socioeconomic status; StructLMM, Structured Linear Mixed Model; Suicide; Trauma.

Abstract

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