Cargando…
Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality
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 suicid...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905234/ https://www.ncbi.nlm.nih.gov/pubmed/33665242 http://dx.doi.org/10.1016/j.ynstr.2021.100309 |
_version_ | 1783655073101905920 |
---|---|
author | Wendt, Frank R. Pathak, Gita A. Levey, Daniel F. Nuñez, Yaira Z. Overstreet, Cassie Tyrrell, Chelsea Adhikari, Keyrun De Angelis, Flavio Tylee, Daniel S. Goswami, Aranyak Krystal, John H. Abdallah, Chadi G. Stein, Murray B. Kranzler, Henry R. Gelernter, Joel Polimanti, Renato |
author_facet | Wendt, Frank R. Pathak, Gita A. Levey, Daniel F. Nuñez, Yaira Z. Overstreet, Cassie Tyrrell, Chelsea Adhikari, Keyrun De Angelis, Flavio Tylee, Daniel S. Goswami, Aranyak Krystal, John H. Abdallah, Chadi G. Stein, Murray B. Kranzler, Henry R. Gelernter, Joel Polimanti, Renato |
author_sort | Wendt, Frank R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7905234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-79052342021-03-03 Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality Wendt, Frank R. Pathak, Gita A. Levey, Daniel F. Nuñez, Yaira Z. Overstreet, Cassie Tyrrell, Chelsea Adhikari, Keyrun De Angelis, Flavio Tylee, Daniel S. Goswami, Aranyak Krystal, John H. Abdallah, Chadi G. Stein, Murray B. Kranzler, Henry R. Gelernter, Joel Polimanti, Renato Neurobiol Stress Original Research Article 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. Elsevier 2021-02-18 /pmc/articles/PMC7905234/ /pubmed/33665242 http://dx.doi.org/10.1016/j.ynstr.2021.100309 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Article Wendt, Frank R. Pathak, Gita A. Levey, Daniel F. Nuñez, Yaira Z. Overstreet, Cassie Tyrrell, Chelsea Adhikari, Keyrun De Angelis, Flavio Tylee, Daniel S. Goswami, Aranyak Krystal, John H. Abdallah, Chadi G. Stein, Murray B. Kranzler, Henry R. Gelernter, Joel Polimanti, Renato Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title | Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title_full | Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title_fullStr | Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title_full_unstemmed | Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title_short | Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
title_sort | sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905234/ https://www.ncbi.nlm.nih.gov/pubmed/33665242 http://dx.doi.org/10.1016/j.ynstr.2021.100309 |
work_keys_str_mv | AT wendtfrankr sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT pathakgitaa sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT leveydanielf sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT nunezyairaz sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT overstreetcassie sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT tyrrellchelsea sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT adhikarikeyrun sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT deangelisflavio sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT tyleedaniels sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT goswamiaranyak sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT krystaljohnh sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT abdallahchadig sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT steinmurrayb sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT kranzlerhenryr sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT gelernterjoel sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality AT polimantirenato sexstratifiedgenebyenvironmentgenomewideinteractionstudyoftraumaposttraumaticstressandsuicidality |