Genomic influences on self-reported childhood maltreatment

Shareefa Dalvie¹, Adam X Maihofer^{2

3

4}, Jonathan R I Coleman^{5

6}, Bekh Bradley^{7

8}, Gerome Breen^{5

6}, Leslie A Brick⁹, Chia-Yen Chen^{10

11

12}, Karmel W Choi^{12

13

14}, Laramie E Duncan¹⁵, Guia Guffanti^{16

17}, Magali Haas¹⁸, Supriya Harnal¹², Israel Liberzon¹⁹, Nicole R Nugent^{9

20}, Allison C Provost¹⁸, Kerry J Ressler^{8

16

17}, Katy Torres^{2

3

4}, Ananda B Amstadter²¹, S Bryn Austin^{16

22

23

24}, Dewleen G Baker^{2

3

25}, Elizabeth A Bolger^{16

17}, Richard A Bryant²⁶, Joseph R Calabrese²⁷, Douglas L Delahanty^{28

29}, Lindsay A Farrer³⁰, Norah C Feeny³¹, Janine D Flory³², David Forbes³³, Sandro Galea³⁴, Aarti Gautam³⁵, Joel Gelernter^{36

37

38}, Rasha Hammamieh³⁹, Marti Jett³⁹, Angela G Junglen²⁸, Milissa L Kaufman^{16

17}, Ronald C Kessler⁴⁰, Alaptagin Khan^{17

40}, Henry R Kranzler^{41

42}, Lauren A M Lebois^{16

17}, Charles Marmar⁴³, Matig R Mavissakalian²⁷, Alexander McFarlane⁴⁴, Meaghan O' Donnell³³, Holly K Orcutt⁴⁵, Robert H Pietrzak^{46

47}, Victoria B Risbrough^{2

3

4}, Andrea L Roberts⁴⁸, Alex O Rothbaum³¹, Peter Roy-Byrne⁴⁹, Ken Ruggiero⁵⁰, Antonia V Seligowski^{16

17}, Christina M Sheerin²¹, Derrick Silove⁵¹, Jordan W Smoller^{10

12

14}, Murray B Stein^{2

25

52}, Martin H Teicher^{16

17}, Robert J Ursano⁵³, Miranda Van Hooff⁴⁴, Sherry Winternitz^{16

17}, Jonathan D Wolff¹⁷, Rachel Yehuda^{32

54}, Hongyu Zhao⁵⁵, Lori A Zoellner⁵⁶, Dan J Stein⁵⁷, Karestan C Koenen^{11

12

58}, Caroline M Nievergelt^{2

3

4}

Affiliations

¹ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. s.dalvie1@uct.ac.za.
² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁴ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁵ King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
⁶ King's College London, NIHR BRC at the Maudsley, London, UK.
⁷ Atlanta VA Health Care System, Mental Health Service Line, Decatur, GA, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁹ Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, MA, USA.
¹¹ Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
¹² Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
¹³ Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA.
¹⁴ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁶ Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
¹⁷ McLean Hospital, Belmont, MA, USA.
¹⁸ Cohen Veterans Bioscience, Cambridge, MA, USA.
¹⁹ Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, USA.
²⁰ Bradley/Hasbro Children's Research Center of Rhode Island Hospital, Providence, RI, USA.
²¹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
²² Harvard School of Public Health, Department of Social and Behavioral Sciences, Boston, MA, USA.
²³ Boston Children's Hospital, Division of Adolescent and Young Adult Medicine, Boston, MA, USA.
²⁴ Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA.
²⁵ Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
²⁶ Department of Psychology, University of New South Wales, Sydney, NSW, Australia.
²⁷ Department of Psychiatry, University Hospitals, Cleveland, OH, USA.
²⁸ Department of Psychological Sciences, Kent State University, Kent, OH, USA.
²⁹ Research and Sponsored Programs, Kent State University, Kent, OH, USA.
³⁰ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³¹ Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA.
³² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
³⁴ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
³⁵ US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.
³⁶ US Department of Veterans Affairs, Department of Psychiatry, West Haven, CT, USA.
³⁷ VA Connecticut Healthcare Center, West Haven, CT, USA.
³⁸ Department of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
³⁹ US Army Medical Research and Materiel Command, USACEHR, Fort Detrick, MD, USA.
⁴⁰ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
⁴¹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴² Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
⁴³ Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁴⁴ University of Adelaide, Centre for Traumatic Stress Studies, Adelaide, SA, Australia.
⁴⁵ Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁴⁶ U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, USA.
⁴⁷ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁴⁸ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Psychiatry, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Nursing and Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
⁵¹ Department of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁵² Veterans Affairs San Diego Healthcare System, Million Veteran Program, San Diego, CA, USA.
⁵³ Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
⁵⁴ Department of Mental Health, James J. Peters VA Medical Center, Bronx, NY, USA.
⁵⁵ Department of Biostatistics, Yale University, New Haven, CT, USA.
⁵⁶ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
⁵⁷ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
⁵⁸ Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA.

PMID: 32066696
PMCID: PMC7026037
DOI: 10.1038/s41398-020-0706-0

Genomic influences on self-reported childhood maltreatment

Shareefa Dalvie et al. Transl Psychiatry. 2020.

. 2020 Jan 27;10(1):38.

doi: 10.1038/s41398-020-0706-0.

Authors

Affiliations

¹ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. s.dalvie1@uct.ac.za.
² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁴ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁵ King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
⁶ King's College London, NIHR BRC at the Maudsley, London, UK.
⁷ Atlanta VA Health Care System, Mental Health Service Line, Decatur, GA, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁹ Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, MA, USA.
¹¹ Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
¹² Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
¹³ Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA.
¹⁴ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁶ Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
¹⁷ McLean Hospital, Belmont, MA, USA.
¹⁸ Cohen Veterans Bioscience, Cambridge, MA, USA.
¹⁹ Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, USA.
²⁰ Bradley/Hasbro Children's Research Center of Rhode Island Hospital, Providence, RI, USA.
²¹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
²² Harvard School of Public Health, Department of Social and Behavioral Sciences, Boston, MA, USA.
²³ Boston Children's Hospital, Division of Adolescent and Young Adult Medicine, Boston, MA, USA.
²⁴ Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA.
²⁵ Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
²⁶ Department of Psychology, University of New South Wales, Sydney, NSW, Australia.
²⁷ Department of Psychiatry, University Hospitals, Cleveland, OH, USA.
²⁸ Department of Psychological Sciences, Kent State University, Kent, OH, USA.
²⁹ Research and Sponsored Programs, Kent State University, Kent, OH, USA.
³⁰ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³¹ Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA.
³² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia.
³⁴ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
³⁵ US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.
³⁶ US Department of Veterans Affairs, Department of Psychiatry, West Haven, CT, USA.
³⁷ VA Connecticut Healthcare Center, West Haven, CT, USA.
³⁸ Department of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
³⁹ US Army Medical Research and Materiel Command, USACEHR, Fort Detrick, MD, USA.
⁴⁰ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
⁴¹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴² Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
⁴³ Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁴⁴ University of Adelaide, Centre for Traumatic Stress Studies, Adelaide, SA, Australia.
⁴⁵ Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁴⁶ U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, USA.
⁴⁷ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁴⁸ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Psychiatry, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Nursing and Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
⁵¹ Department of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁵² Veterans Affairs San Diego Healthcare System, Million Veteran Program, San Diego, CA, USA.
⁵³ Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
⁵⁴ Department of Mental Health, James J. Peters VA Medical Center, Bronx, NY, USA.
⁵⁵ Department of Biostatistics, Yale University, New Haven, CT, USA.
⁵⁶ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
⁵⁷ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
⁵⁸ Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA.

PMID: 32066696
PMCID: PMC7026037
DOI: 10.1038/s41398-020-0706-0

Abstract

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h²_snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h²_snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10^-8, FOXP1; rs10262462, p = 3.24 × 10^-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h²_snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r² = 0.0025; p = 1.8 × 10^-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r_g = 0.70, p = 4.65 × 10^-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

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Conflict of interest statement

H.R.K. is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which in the last 3 years was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. H.R.K. and J.G. are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. In the past 3 years, D.J.S. has received research grants and/or consultancy honoraria from Lundbeck and Sun. In the past 3 years, R.C.K. received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Sage Pharmaceuticals, Shire, Takeda; and served on an advisory board for the Johnson & Johnson. Services Inc. Lake Nona Life Project. Kessler is a co-owner of DataStat, Inc., a market research firm that carries out healthcare research. M.B.S. has in the past 3 years been a consultant for Aptinyx, Bionomics, Dart Neuroscience, Janssen, Jazz Pharmaceuticals, Neurocrine Biosciences, Oxeia Biopharmaceuticals, and Pfizer. R.Y. is a co-inventor of the following patent application: “Genes associated with posttraumatic-stress disorder. European Patent# EP 2334816 B1.

Figures

**Fig. 1. Manhattan plot of UKBB GWAS for childhood maltreatment, showing the top variants.**
The horizontal line represents genome-wide significance at p < 5 × 10⁻⁸.

**Fig. 2**
Top ten genetic correlations between several groups of traits (from psychiatric, anthropomorphic, smoking behavior, reproductive, aging, education, autoimmune, and cardio-metabolic categories) and childhood maltreatment (meta-analysis).

See this image and copyright information in PMC

References

1. Child maltreatment. Global estimates. http://apps.who.int/gho/data/view.main.VIOLENCECHILDMALTREATMENTv (2016).
1. McLaughlin KA, et al. Childhood adversities and post-traumatic stress disorder: evidence for stress sensitisation in the World Mental Health Surveys. Br. J. Psychiatry. 2017;211:280–288. - PMC - PubMed
1. Copeland WE, et al. Association of childhood trauma exposure with adult psychiatric disorders and functional outcomes. JAMA Network Open. 2018;1:e184493–e184493. - PMC - PubMed
1. Basu A, McLaughlin KA, Misra S, Koenen KC. Childhood maltreatment and health impact: the examples of cardiovascular disease and type 2 diabetes mellitus in adults. Clin. Psychol. 2017;24:125–139. - PMC - PubMed
1. Suglia SF, et al. Childhood and adolescent adversity and cardiometabolic outcomes: a scientific statement from the American Heart Association. Circulation. 2018;137:e15–e28. - PMC - PubMed

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Genomic influences on self-reported childhood maltreatment

Affiliations

Genomic influences on self-reported childhood maltreatment

Authors

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Abstract

Conflict of interest statement

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