Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals: A Meta-Analysis

Wonuola A Akingbuwa, Anke R Hammerschlag, Eshim S Jami, Bart Baselmans, Fiona A Hagenbeek, Jouke-Jan Hottenga, Hamdi Mbarek, Dorret I Boomsma, Michel G Nivard, Meike Bartels, Christel M Middeldorp, Bipolar Disorder and Major Depressive Disorder Working Groups of the Psychiatric Genomics Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Importance: Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits.

Objective: To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders.

Design, Setting, and Participants: This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019.

Exposures: Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI).

Main Outcomes and Measures: Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater.

Results: The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (β estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (β, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δβ, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δβ, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δβ, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δβ, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δβ, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008).

Conclusions and Relevance: Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

Original languageEnglish
Pages (from-to)715-728
Number of pages14
JournalJAMA Psychiatry
Volume77
Issue number7
DOIs
Publication statusPublished - Jul 2020

Funding

Jami, and Hagenbeek have reported grants from the European Union Horizon 2020 research and innovation programme, Netherlands Organisation for Scientific Research (NWO), Netherlands Organisation for Health Research and Development (ZonMw), Biobanking and Biomolecular Resources Research Infrastructure, European Union FP7, European Research Council, National Institute of Health (NIH), and the National Institute of Mental Health (NIMH). Mr Allegrini reports receiving grants from European Union's Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions (MSCA-ITN-2016; Innovative Training Networks grant 721567). Dr Askeland reports grants from Research Council of Norway during the conduct of the study. Dr Bartels reports grants from EU Marie Curie Training Grant and the European Research Council consolidator grant. Dr Lewis reports grants from NIMH during the conduct of the study and sits on the Scientific Advisory Board of Myriad Neuroscience outside the submitted work. Dr Middeldorp reports grants from NWO, the European Union, the NIH, and the Avera Institute of Human Genetics. Dr Nivard reports grants from ZonMw and NWO. No other disclosures were reported. We thank all cohort members and researchers who have participated in the study. We also wish to acknowledge the work of the NFBC project center. NFBC1986 study has received financial support from EU QLG1-CT-2000-01643 (EUROBLCS) Grant no. E51560, NorFA Grant no. 731, 20056, 30167, USA / NIHH 2000 G DF682 Grant no. 50945, NIHM/MH063706, H2020-633595 DynaHEALTH action and Academy of Finland EGEA-project (285547). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authority and KG Jebsen Stiftelsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway health Authorities (Helse Vest). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Data access for this project was funded by the Research Council of Norway project 262177. TEDS is supported by a program grant to RP from the UK Medical Research Council (MR/M021475/1 and previously G0901245), with additional support from the US National Institutes of Health (AG046938). The research leading to these results has also received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ grant agreement n° 602768. SS is supported by the MRC/IoPPN Excellence Award and by the US National Institutes of Health (AG046938). High performance computing facilities were funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). The Child and Adolescent Twin Study in Sweden study was supported by the Swedish Council for Working Life, and the Swedish Research Council. The research leading to these results has also received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 602768. CATSS is a part of the Swedish Twin Registry, managed by Karolinska Institutet and receiving funding through the Swedish Research Council under the grant no 2017-00641. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. funding from the European Union’s Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions (MSCA-ITN-2016) Innovative Training Networks (grant 721567 [Ms Akingbuwa, Dr Jami, Mrs Allegrini, Dr Karhunen, and Ms Diemer]). The Psychiatric Genomics Consortium has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (grants U01 MH109528 and U01 MH1095320). Dr Hammerschlag is supported by the Children’s Hospital Foundation and University of Queensland strategic funding. Dr Sallis is a member of the MRC Integrative Epidemiology Unit at the University of Bristol (grant MC_UU_00011/7). Ms Askeland is supported by the Research Council of Norway (grant 274611). Dr Havdahl is supported by the South-Eastern Norway Regional Health Authority (grant 2018059) and is a member of the MRC Integrative Epidemiology Unit at the University of Bristol (grant MC_UU_00011/1). Dr Thapar is supported by the Wellcome Trust and MRC. Dr Boomsma is supported by Koninklijke Nederlandse Akademie van Wetenschappen Academy Professor Award (grant PAH/6635). Dr Reichborn-Kjennerud is supported by the Research Council of Norway (grant 274611). Dr Magnus is supported by the Research Council of Norway (grant 262700). Dr Rimfeld is funded by a Sir Henry Wellcome Postdoctoral Fellowship. Dr Ystrom is supported by the Research Council of Norway (grants 262177 and 288083). Mr Lundstrom is funded by the Child and Adolescent Twin Study in Sweden is supported by Swedish Research Council (Medicine, Humanities and Social Science, and SIMSAM), Funds under the ALF agreement, and the Swedish Research Council for Health, Working Life and Welfare (FORTE). Dr Munafò is a member of the MRC Integrative Epidemiology Unit at the University of Bristol (grant MC_UU_00011/7). Dr Plomin is supported by a Medical Research Council Professorship award (grant G19/2). Dr Tiemeier received funding from the Netherlands Organization for Health Research and Development (grant 016.VICI.170.200). Dr Nivard is supported by ZonMw (grants 531003014 and 849200011). Dr Bartels is funded by an ERC Consolidator Grant (WELL-BEING; grant 771057). Data collection in the NTR was supported by NWO: Twin-family database for behavior genetics and genomics studies (480-04-³6SLQR]DSUHPLH´ 1:2 63, -464-³*HQHWLF DQG )DPLO\ LQIOXHQFHV RQ $GROHVFHQW psychopathRORJ\ DQG :HOOQHVV´ 1:2 -06-³$ WZLQ-VLE VWXG\ RI DGROHVFHQW ZHOOQHVV´ 1:2-VENI 451-04-=RQ0: ³*HQHWLF LQIOXHQFHV RQ VWDELOLW\ DQG FKDQJH LQ SV\FKRSDWKRORJ\ IURP FKLOGKRRG WR \RXQJ DGXOWKRRG´ -10-³1HWKHUODQGV 7ZLQ 5HJLVWU\ 5HSRVLWRU\´ -15-³%LREDQNLQJ DQG %LRPROHFXODU 5HVRXUFHV 5HVHDUFK ,QIUDVWUXFWXUH´ %%05, ±NL (184.021.007 and 184.033.111). We acknowledge FP7-HEALTH-F4-2007, grant agreement no 201413 (ENGAGE), and the FP7/2007-2013 funded ACTION (grant agreement no 602768) and the European Research Council (ERC-230374). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995).

FundersFunder number
Academy of Finland EGEA-project285547
Avera Institute
Avera Institute of Human Genetics
FP7-HEALTH-F4-2007FP7/2007-2013, 201413
GSTTTR130505
KG Jebsen Stiftelsen
NIHHDF682, H2020-633595, NIHM/MH063706, 50945
Netherlands Organization for Health Research and Development016
NorFA30167, 20056, 731
South East Norway Health Authority
Swedish Council for Working Life
Swedish Research Council (Medicine, Humanities and Social Science
University Hospitals Bristol National Health Service Foundation Trust
Western Norway health Authorities
National Institutes of Health1RC2 MH089951, 1RC2 MH089995, AG046938, MH081802, R01 HD042157-01A1
National Institute of Mental HealthU01MH109528, U24 MH068457-06
National Institute on Drug AbuseU01 MH1095320
Stiftelsen Kristian Gerhard Jebsen
Wellcome Trust102215/2/13/2
Horizon 2020 Framework Programme
H2020 Marie Skłodowska-Curie ActionsMSCA-ITN-2016, 721567
Seventh Framework Programme602768
Children’s Hospital Foundation
Maudsley Charity
Institute of Psychiatry, Psychology and Neuroscience, King’s College London
Trond Mohn stiftelse
Medical Research CouncilG0901245, G19/2, MR/M021475/1
National Institute for Health Research
European CommissionQLG1-CT-2000-01643, E51560
European Research Council771057, ERC-230374
University of BristolMC_UU_00011/1
Koninklijke Nederlandse Akademie van Wetenschappen262177, PAH/6635, 288083, 262700
University of Queensland
ZonMw531003014, 849200011
Bundesministerium für Bildung und Forschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Helse- og Omsorgsdepartementet
Karolinska Institutet2017-00641
Vetenskapsrådet
Seventh Framework Programme
Universitetet i Bergen
Norges forskningsråd223273, 229624, 274611
Helse Sør-Øst RHF2018059
Forskningsrådet om Hälsa, Arbetsliv och Välfärd
Horizon 2020
Novo Nordisk Fonden
ULB Center for Diabetes Research

    Keywords

    • Childhood psychopathology
    • Developmental psychopathology
    • Genetics
    • polygenic risk score (PRS)
    • Meta analysis
    • Generation R
    • TEDS
    • CATSS
    • NFBC86
    • ALSPAC
    • NTR
    • MoBa

    Cohort Studies

    • Netherlands Twin Register (NTR)

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