Abstract
To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
| Original language | English (US) |
|---|---|
| Article number | 107716 |
| Journal | Cell Reports |
| Volume | 31 |
| Issue number | 9 |
| DOIs | |
| State | Published - Jun 2 2020 |
Keywords
- GWAS
- PTSD
- blood
- civilian
- glucocorticoid
- military
- prefrontal cortex
- sex
- splicing
- transcriptomic imputation
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts. / PTSD Working Group of Psychiatric Genomics Consortium.
In: Cell Reports, Vol. 31, No. 9, 107716, 02.06.2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts
AU - PTSD Working Group of Psychiatric Genomics Consortium
AU - Huckins, Laura M.
AU - Chatzinakos, Chris
AU - Breen, Michael S.
AU - Hartmann, Jakob
AU - Klengel, Torsten
AU - da Silva Almeida, Ana C.
AU - Dobbyn, Amanda
AU - Girdhar, Kiran
AU - Hoffman, Gabriel E.
AU - Klengel, Claudia
AU - Logue, Mark W.
AU - Lori, Adriana
AU - Maihofer, Adam X.
AU - Morrison, Filomene G.
AU - Nguyen, Hoang T.
AU - Park, Yongjin
AU - Ruderfer, Douglas
AU - Sloofman, Laura G.
AU - van Rooij, Sanne J.H.
AU - Baker, Dewleen G.
AU - Chen, Chia Yen
AU - Cox, Nancy
AU - Duncan, Laramie E.
AU - Geyer, Mark A.
AU - Glatt, Stephen J.
AU - Im, Hae Kyung
AU - Risbrough, Victoria B.
AU - Smoller, Jordan W.
AU - Stein, Dan J.
AU - Yehuda, Rachel
AU - Liberzon, Israel
AU - Koenen, Karestan C.
AU - Jovanovic, Tanja
AU - Kellis, Manolis
AU - Miller, Mark W.
AU - Bacanu, Silviu Alin
AU - Nievergelt, Caroline M.
AU - Buxbaum, Joseph D.
AU - Sklar, Pamela
AU - Ressler, Kerry J.
AU - Stahl, Eli A.
AU - Daskalakis, Nikolaos P.
N1 - Funding Information: We thank the research participants worldwide who shared their life experiences and biological samples with the PGC-PTSD investigators. We thank Jessica Johnson, MPH, for formatting suggestions about the graphical abstract. PGC-PTSD was funded by Cohen Veterans Bioscience , the National Institute of Mental Health ( NIMH) / U.S. Army Medical Research and Materiel Command grant R01MH106595 , and One Mind Institute to I.L., K.C.K., C.M.N., and K.J.R.; and was additionally supported by NIMH grant U01MH109539 to the Psychiatric Genomics Consortium. 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 UK Biobank resource under application number 16577. MRS and MRS-II (including gene expression data) were funded by the Marine Corps and Navy Bureau of Medicine and Surgery , and VA Health Research and Development . L.M.H. was supported by NIMH grant R01MH118278 , a 2017 NARSAD Young Investigator grant from Brain & Behavior Research Foundation, and a Faculty Scholar Award from Seaver Foundation . C.C. was supported by the 2019 Seed Grant from Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (NIMH P50MH115874 ). H.K.I. was supported by two NIMH grants ( R01MH107666 , R01MH101820) , and National Institute of Diabetes and Digestive and Kidney Diseases grant P30DK20595 . P.S. and E.A.S. were supported by a NIMH grant U01MH109536 . N.P.D. was supported by a 2015 and a 2018 NARSAD Young Investigator grants from BBRF, a Jonathan Edward Brooking mental health research fellowship from McLean Hospital and an appointed KL2 award from Harvard Catalyst | The Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences KL2TR002542 , UL1TR002541 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. Funding Information: We thank the research participants worldwide who shared their life experiences and biological samples with the PGC-PTSD investigators. We thank Jessica Johnson, MPH, for formatting suggestions about the graphical abstract. PGC-PTSD was funded by Cohen Veterans Bioscience, the National Institute of Mental Health (NIMH)/U.S. Army Medical Research and Materiel Command grant R01MH106595, and One Mind Institute to I.L. K.C.K. C.M.N. and K.J.R.; and was additionally supported by NIMH grant U01MH109539 to the Psychiatric Genomics Consortium. 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 UK Biobank resource under application number 16577. MRS and MRS-II (including gene expression data) were funded by the Marine Corps and Navy Bureau of Medicine and Surgery, and VA Health Research and Development. L.M.H. was supported by NIMH grant R01MH118278, a 2017 NARSAD Young Investigator grant from Brain & Behavior Research Foundation, and a Faculty Scholar Award from Seaver Foundation. C.C. was supported by the 2019 Seed Grant from Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (NIMH P50MH115874). H.K.I. was supported by two NIMH grants (R01MH107666, R01MH101820), and National Institute of Diabetes and Digestive and Kidney Diseases grant P30DK20595. P.S. and E.A.S. were supported by a NIMH grant U01MH109536. N.P.D. was supported by a 2015 and a 2018 NARSAD Young Investigator grants from BBRF, a Jonathan Edward Brooking mental health research fellowship from McLean Hospital and an appointed KL2 award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences KL2TR002542, UL1TR002541). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. Conceptualization, L.M.H. J.D.B. P.S. E.A.S. and N.P.D.; Data Curation, L.M.H. C.C. M.S.B. J.H. T.K. C.K. M.W.L. A.L. F.G.M. Y.P. L.G.S. S.J.H.v.R. D.G.B. L.E.D. S.J.G. A.X.M. T.J. C.M.N. and N.P.D.; Formal Analysis, L.M.H. C.C. and N.P.D.; Funding Acquisition, L.M.H. I.L. K.C.K. C.M.N. J.D.B. P.S. K.J.R. E.A.S. and N.P.D.; Investigation, L.M.H. C.C. M.S.B. J.H. T.K. A.C.d.S.A. A.D. K.G. G.E.H. C.K. M.W.L. A.L. F.G.M. H.T.N. Y.P. S.J.H.v.R. T.J. M.K. M.W.M. S.-A.B. C.M.N. P.S. K.J.R. E.A.S. and N.P.D.; Methodology, L.M.H. C.C. M.S.B. J.H. T.K. A.C.d.S.A. A.D. K.G. G.E.H. C.K. A.L. F.G.M. Y.P. S.J.H.v.R. N.C. H.K.I. K.J.R. E.A.S. and N.P.D.; Project Administration, L.M.H. E.A.S. and N.P.D.; Resources, D.G.B. M.A.G. S.J.G. H.K.I. V.B.R. M.W.M. C.M.N. P.S. K.J.R. E.A.S. and N.P.D.; Software, L.M.H. C.C. M.S.B. A.D. Y.P. H.K.I. E.A.S. and N.P.D.; Supervision, L.M.H. T.K. T.J. M.K. M.W.M. S.-A.B. C.M.N. J.D.B. P.S. K.J.R. E.A.S. and N.P.D.; Validation, L.M.H. C.C. M.S.B. J.H. T.K. A.C.d.S.A. C.K. M.W.L. A.L. F.G.M. Y.P. S.J.v.R. T.J. C.M.N. K.J.R. and N.P.D.; Visualization, L.M.H. C.C. M.S.B. J.H. A.C.d.S.A. and N.P.D.; Writing ? Original Draft, L.M.H. and N.P.D.; Graphical Abstract, N.P.D.; Writing ? Review and Editing, L.M.H. C.C. M.S.B. J.H. T.K. A.C.d.S.A. A.D. K.G. G.E.H. C.K. M.W.L. A.L. F.G.M. H.T.N. Y.P. D.R. L.G.S. S.J.H.v.R. D.G.B. C.-Y.C. N.C. L.E.D. M.A.G. S.J.G. H.K.I. A.X.M. V.B.R. J.W.S. D.J.S. R.Y. I.L. K.C.K. T.J. M.K. M.W.M. S.-A.B. C.M.N. J.D.B. P.S. K.J.R. E.A.S. and N.P.D. J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. D.J.S. has received research grants and/or consultancy honoraria from Biocodex, Lundbeck, and Sun. R.Y. is a co-inventor of the following patent: ?Genes associated with posttraumatic-stress disorder, WO 2010029176 A1.? I.L. has been a consultant for ARMGO Pharmaceuticals, Sunovion Pharmaceuticals, and Trimaran Pharma. K.J.R. has received consulting income from Alkermes and is on scientific advisory boards for Janssen, Verily, and Resilience Therapeutics. He has also received sponsored research support from Takeda and Brainsway. N.P.D. has held a part-time paid position at Cohen Veteran Bioscience. He has also been a consultant for Sunovion Pharmaceuticals. Publisher Copyright: © 2020 The Author(s)
PY - 2020/6/2
Y1 - 2020/6/2
N2 - To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
AB - To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
KW - GWAS
KW - PTSD
KW - blood
KW - civilian
KW - glucocorticoid
KW - military
KW - prefrontal cortex
KW - sex
KW - splicing
KW - transcriptomic imputation
UR - http://www.scopus.com/inward/record.url?scp=85085571507&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085571507&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.107716
DO - 10.1016/j.celrep.2020.107716
M3 - Article
C2 - 32492425
AN - SCOPUS:85085571507
VL - 31
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 9
M1 - 107716
ER -