Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

doi:10.1038/mp.2017.77

Meta-Analysis

. 2018 Mar;23(3):666-673.

doi: 10.1038/mp.2017.77. Epub 2017 Apr 25.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

L E Duncan^{1

2

3}, A Ratanatharathorn⁴, A E Aiello⁵, L M Almli⁶, A B Amstadter⁷, A E Ashley-Koch⁸, D G Baker^{9

10}, J C Beckham^{11

12}, L J Bierut¹³, J Bisson¹⁴, B Bradley^{15

16}, C-Y Chen^{3

17

18}, S Dalvie¹⁹, L A Farrer²⁰, S Galea²¹, M E Garrett⁸, J E Gelernter²², G Guffanti^{18

23}, M A Hauser⁸, E O Johnson²⁴, R C Kessler²⁵, N A Kimbrel^{11

12}, A King²⁶, N Koen^{27

28}, H R Kranzler²⁹, M W Logue^{30

31}, A X Maihofer³², A R Martin^{2

3}, M W Miller^{30

33}, R A Morey^{12

34}, N R Nugent^{35

36}, J P Rice³⁷, S Ripke^{2

3

38}, A L Roberts³⁹, N L Saccone⁴⁰, J W Smoller^{2

17}, D J Stein^{27

28}, M B Stein^{32

41

42}, J A Sumner⁴³, M Uddin⁴⁴, R J Ursano⁴⁵, D E Wildman⁴⁶, R Yehuda^{47

48}, H Zhao⁴⁹, M J Daly^{2

3}, I Liberzon^{26

50}, K J Ressler^{18

23}, C M Nievergelt^{9

10}, K C Koenen^{2

17

51}

Affiliations

¹ Department of Psychiatry, Stanford University, Stanford, CA, USA.
² Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Boston, MA, USA.
³ The Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Epidemiology, Columbia University, New York, NY, USA.
⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁷ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Department of Medicine, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
⁹ Veterans Affairs San Diego Healthcare System and Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
¹⁰ Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
¹¹ Veterans Affairs Durham Healthcare System, Durham, NC, USA.
¹² Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
¹³ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
¹⁴ Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹⁵ Atlanta VA Medical Center, Atlanta, GA, USA.
¹⁶ Department of Psychiatry, Emory University, Atlanta, GA, USA.
¹⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Psychiatry, Harvard University, Cambridge, MA, USA.
¹⁹ Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
²⁰ Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
²¹ Boston University School of Public Health, Boston, MA, USA.
²² Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare System, New Haven, CT, USA.
²³ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
²⁴ RTI International, Research Triangle Park, NC, USA.
²⁵ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
²⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²⁸ MRC Unit on Anxiety & Stress Disorders, Groote Schuur Hospital, Cape Town, South Africa.
²⁹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
³⁰ VA Boston Healthcare System, Jamaica Plain, MA, USA.
³¹ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³² Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
³³ Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
³⁴ Durham VA Medical Center, Durham, NC, USA.
³⁵ Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, Providence, RI, USA.
³⁶ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
³⁷ Department of Psychiatry, Washington University, St Louis, MO, USA.
³⁸ Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
³⁹ Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health Cambridge, MA, USA.
⁴⁰ Department of Genetics, Washington University, St Louis, MO, USA.
⁴¹ Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁴² Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
⁴³ Center for Cardiovascular Behavioral Health, Columbia University Medical Center, New York, NY, USA.
⁴⁴ Department of Psychology and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁴⁵ Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁴⁶ Department of Molecular & Integrative Physiology and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁴⁷ James J. Peters Bronx Veterans Affairs and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Bronx, NY, USA.
⁴⁸ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Bronx, NY, USA.
⁴⁹ Department of Biostatistics, Yale University, New Haven, CT, USA.
⁵⁰ VA Ann Arbor Health System, Ann Arbor, MI, USA.
⁵¹ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Cambridge, MA, USA.

PMID: 28439101
PMCID: PMC5696105
DOI: 10.1038/mp.2017.77

Meta-Analysis

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

L E Duncan et al. Mol Psychiatry. 2018 Mar.

. 2018 Mar;23(3):666-673.

doi: 10.1038/mp.2017.77. Epub 2017 Apr 25.

Authors

Affiliations

¹ Department of Psychiatry, Stanford University, Stanford, CA, USA.
² Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Boston, MA, USA.
³ The Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Epidemiology, Columbia University, New York, NY, USA.
⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁷ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Department of Medicine, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
⁹ Veterans Affairs San Diego Healthcare System and Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
¹⁰ Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
¹¹ Veterans Affairs Durham Healthcare System, Durham, NC, USA.
¹² Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
¹³ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
¹⁴ Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹⁵ Atlanta VA Medical Center, Atlanta, GA, USA.
¹⁶ Department of Psychiatry, Emory University, Atlanta, GA, USA.
¹⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Psychiatry, Harvard University, Cambridge, MA, USA.
¹⁹ Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
²⁰ Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
²¹ Boston University School of Public Health, Boston, MA, USA.
²² Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare System, New Haven, CT, USA.
²³ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
²⁴ RTI International, Research Triangle Park, NC, USA.
²⁵ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
²⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²⁸ MRC Unit on Anxiety & Stress Disorders, Groote Schuur Hospital, Cape Town, South Africa.
²⁹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
³⁰ VA Boston Healthcare System, Jamaica Plain, MA, USA.
³¹ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³² Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
³³ Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
³⁴ Durham VA Medical Center, Durham, NC, USA.
³⁵ Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, Providence, RI, USA.
³⁶ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
³⁷ Department of Psychiatry, Washington University, St Louis, MO, USA.
³⁸ Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
³⁹ Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health Cambridge, MA, USA.
⁴⁰ Department of Genetics, Washington University, St Louis, MO, USA.
⁴¹ Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁴² Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
⁴³ Center for Cardiovascular Behavioral Health, Columbia University Medical Center, New York, NY, USA.
⁴⁴ Department of Psychology and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁴⁵ Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁴⁶ Department of Molecular & Integrative Physiology and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁴⁷ James J. Peters Bronx Veterans Affairs and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Bronx, NY, USA.
⁴⁸ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Bronx, NY, USA.
⁴⁹ Department of Biostatistics, Yale University, New Haven, CT, USA.
⁵⁰ VA Ann Arbor Health System, Ann Arbor, MI, USA.
⁵¹ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Cambridge, MA, USA.

PMID: 28439101
PMCID: PMC5696105
DOI: 10.1038/mp.2017.77

Abstract

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h²_SNP) for European-American females of 29% that is similar to h²_SNP for schizophrenia and is substantially higher than h²_SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

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Conflict of interest statement

Dr Kranzler has been an advisory board member, consultant or CME speaker for Indivior, Lundbeck and Otsuka. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative that is supported by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer and XenoPort. Dr Ressler is a founding member of Extinction Pharmaceuticals to develop D-Cycloserine to augment the effectiveness of psychotherapy. He has received no equity or income from this relationship within the past 3 years. Dr Ressler is also on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt-Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project and the Anxiety and Depression Association of America. He holds patents for use of D-cycloserine and psychotherapy, targeting PAC1 receptor for extinction, targeting tachykinin 2 for prevention of fear and targeting angiotensin to improve extinction of fear. He receives or has received research funding from NIMH, HHMI, NARSAD, and the Burroughs Wellcome Foundation. In the past 3 years, Dr Dan J Stein has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier and Sun. Dr Murray Stein reports receiving in the past 3 years consultant fees from Actelion, Janssen, Dart Neuroscience, Healthcare Management Technologies and Pfizer. He also has an equity interest in Resilience Therapeutics and Oxeia Biopharmaceuticals. He has also received editorial honoraria from Biological Psychiatry and Up-To-Date. Dr Bierut is listed as an inventor on Issued US Patent 8,080,371, ‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. In the past 3 years, Dr Kessler received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Shire and Takeda; and has served on an advisory board for the Johnson & Johnson Services Lake Nona Life Project. Kessler is a co-owner of DataStat, a market research firm that carries out health-care research. In the past 3 years, Dr Liberzon has been a consultant for ARMGO Pharmaceutical, Sunovion Pharmaceutical and Trimaran Pharma. The remaining authors declare no conflicts of interest.

Figures

**Figure 1**
Study design for phase 1 PGC-PTSD: (a) single variant GWAS and meta-analyses (b) polygenic analyses. (a) Each of the 19 gray boxes represents one ancestry-assigned data set/GWAS. Within-ancestry meta-analyses were followed by the transethnic meta-analysis. (b) Blue boxes denote polygenic analyses. LDSC could not be applied to the African-American (AA) subsample. Latino/Hispanic (LA) and South African samples were deemed too small for polygenic analyses. GWAS, genome-wide association study; LDSC, linkage disequilibrium score regression; PGC-PTSD, Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group.

**Figure 2**
Ancestral composition for phase 1 of PGC-PTSD and principal components (PC) plot of individuals’ data. (a) PGC-PTSD (left) compared with the largest psychiatric meta-analyses (center) and estimated world ancestry (right). (b) Plot of first two principal components and assigned ancestry according to the protocol described in the text. Each dot is one individual. GWAS, genome-wide association study; PGC-PTSD, Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group.

**Figure 3**
PTSD SNP-chip heritability (h²_SNP) overall and for males and females separately and comparison with other psychiatric disorders. Gray bars denote PTSD heritability estimates. Slashed bars reflect SCZ, BIP and MDD heritability estimates calculated using LDSC as applied to published data.^{, ,} Red lines denote twin study heritability estimates, see Discussion. European-American (EA) samples only per description in text; error bars reflect s.e. BIP, bipolar disorder; LDSC, linkage disequilibrium score regression; MDD, major depressive disorder; PTSD, posttraumatic stress disorder; SCZ, schizophrenia; SNP, single-nucleotide polymorphism.

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References

1. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med 2005; 352: 2515–2523. - PMC - PubMed
1. Davidson JR. Trauma: the impact of post-traumatic stress disorder. J Psychopharmacol Oxf Engl 2000; 14(2 Suppl 1): S5–S12. - PubMed
1. Herman J. Trauma and Recovery: The Aftermath of Violence—From Domestic Abuse to Political Terror. Basic Books: New York, 1997.
1. Myers C. A final contribution to the study of shell shock - being a consideration of unsettled points needing investigation. Lancet 1915; 185: 316–330.
1. Department of Veterans Affairs. National Research Action Plan: Responding to the Executive Order Improving Access to Mental Health Services for Veterans, Service Members and Military Families. CreateSpace Independent Publishing Platform, 2014.

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[1] Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med 2005; 352: 2515–2523. - PMC - PubMed

[2] Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med 2005; 352: 2515–2523. - PMC - PubMed

[3] Davidson JR. Trauma: the impact of post-traumatic stress disorder. J Psychopharmacol Oxf Engl 2000; 14(2 Suppl 1): S5–S12. - PubMed

[4] Davidson JR. Trauma: the impact of post-traumatic stress disorder. J Psychopharmacol Oxf Engl 2000; 14(2 Suppl 1): S5–S12. - PubMed

[5] Herman J. Trauma and Recovery: The Aftermath of Violence—From Domestic Abuse to Political Terror. Basic Books: New York, 1997.

[6] Herman J. Trauma and Recovery: The Aftermath of Violence—From Domestic Abuse to Political Terror. Basic Books: New York, 1997.

[7] Myers C. A final contribution to the study of shell shock - being a consideration of unsettled points needing investigation. Lancet 1915; 185: 316–330.

[8] Myers C. A final contribution to the study of shell shock - being a consideration of unsettled points needing investigation. Lancet 1915; 185: 316–330.

[9] Department of Veterans Affairs. National Research Action Plan: Responding to the Executive Order Improving Access to Mental Health Services for Veterans, Service Members and Military Families. CreateSpace Independent Publishing Platform, 2014.

[10] Department of Veterans Affairs. National Research Action Plan: Responding to the Executive Order Improving Access to Mental Health Services for Veterans, Service Members and Military Families. CreateSpace Independent Publishing Platform, 2014.

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Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

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Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

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