Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Eshim S. Jami; Anke R. Hammerschlag; Hill F. Ip; Andrea G. Allegrini; Beben Benyamin; Richard Border; Elizabeth W. Diemer; Chang Jiang; Ville Karhunen; Yi Lu; Qing Lu; Travis T. Mallard; Pashupati P. Mishra; Ilja M. Nolte; Teemu Palviainen; Roseann E. Peterson; Hannah M. Sallis; Andrey A. Shabalin; Ashley E. Tate; Elisabeth Thiering; Natàlia Vilor-Tejedor; Carol Wang; Ang Zhou; Daniel E. Adkins; Silvia Alemany; Helga Ask; Qi Chen; Robin P. Corley; Erik A. Ehli; Luke M. Evans; Alexandra Havdahl; Fiona A. Hagenbeek; Christian Hakulinen; Anjali K. Henders; Jouke Jan Hottenga; Tellervo Korhonen; Abdullah Mamun; Shelby Marrington; Alexander Neumann; Kaili Rimfeld; Fernando Rivadeneira; Judy L. Silberg; Catharina E. van Beijsterveldt; Eero Vuoksimaa; Alyce M. Whipp; Xiaoran Tong; Ole A. Andreassen; Dorret I. Boomsma; Sandra A. Brown; S. Alexandra Burt; William Copeland; Danielle M. Dick; K. Paige Harden; Kathleen Mullan Harris; Catharina A. Hartman; Joachim Heinrich; John K. Hewitt; Christian Hopfer; Elina Hypponen; Marjo Riitta Jarvelin; Jaakko Kaprio; Liisa Keltikangas-Järvinen; Kelly L. Klump; Kenneth Krauter; Ralf Kuja-Halkola; Henrik Larsson; Terho Lehtimäki; Paul Lichtenstein; Sebastian Lundström; Hermine H. Maes; Per Magnus; Marcus R. Munafò; Jake M. Najman; Pål R. Njølstad; Albertine J. Oldehinkel; Craig E. Pennell; Robert Plomin; Ted Reichborn-Kjennerud; Chandra Reynolds; Richard J. Rose; Andrew Smolen; Harold Snieder; Michael Stallings; Marie Standl; Jordi Sunyer; Henning Tiemeier; Sally J. Wadsworth; Tamara L. Wall; Andrew J.O. Whitehouse; Gail M. Williams; Eivind Ystrøm; Michel G. Nivard; Meike Bartels; Christel M. Middeldorp

doi:10.1016/j.jaac.2021.11.035

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Eshim S. Jami^*, Anke R. Hammerschlag, Hill F. Ip, Andrea G. Allegrini, Beben Benyamin, Richard Border, Elizabeth W. Diemer, Chang Jiang, Ville Karhunen, Yi Lu, Qing Lu, Travis T. Mallard, Pashupati P. Mishra, Ilja M. Nolte, Teemu Palviainen, Roseann E. Peterson, Hannah M. Sallis, Andrey A. Shabalin, Ashley E. Tate, Elisabeth ThieringNatàlia Vilor-Tejedor, Carol Wang, Ang Zhou, Daniel E. Adkins, Silvia Alemany, Helga Ask, Qi Chen, Robin P. Corley, Erik A. Ehli, Luke M. Evans, Alexandra Havdahl, Fiona A. Hagenbeek, Christian Hakulinen, Anjali K. Henders, Jouke Jan Hottenga, Tellervo Korhonen, Abdullah Mamun, Shelby Marrington, Alexander Neumann, Kaili Rimfeld, Fernando Rivadeneira, Judy L. Silberg, Catharina E. van Beijsterveldt, Eero Vuoksimaa, Alyce M. Whipp, Xiaoran Tong, Ole A. Andreassen, Dorret I. Boomsma, Sandra A. Brown, S. Alexandra Burt, William Copeland, Danielle M. Dick, K. Paige Harden, Kathleen Mullan Harris, Catharina A. Hartman, Joachim Heinrich, John K. Hewitt, Christian Hopfer, Elina Hypponen, Marjo Riitta Jarvelin, Jaakko Kaprio, Liisa Keltikangas-Järvinen, Kelly L. Klump, Kenneth Krauter, Ralf Kuja-Halkola, Henrik Larsson, Terho Lehtimäki, Paul Lichtenstein, Sebastian Lundström, Hermine H. Maes, Per Magnus, Marcus R. Munafò, Jake M. Najman, Pål R. Njølstad, Albertine J. Oldehinkel, Craig E. Pennell, Robert Plomin, Ted Reichborn-Kjennerud, Chandra Reynolds, Richard J. Rose, Andrew Smolen, Harold Snieder, Michael Stallings, Marie Standl, Jordi Sunyer, Henning Tiemeier, Sally J. Wadsworth, Tamara L. Wall, Andrew J.O. Whitehouse, Gail M. Williams, Eivind Ystrøm, Michel G. Nivard, Meike Bartels, Christel M. Middeldorp

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INT_overall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n_effective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|r_g| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |r_g| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Original language	English
Pages (from-to)	934-945
Number of pages	12
Journal	Journal of the American Academy of Child and Adolescent Psychiatry
Volume	61
Issue number	7
Early online date	1 Apr 2022
DOIs	https://doi.org/10.1016/j.jaac.2021.11.035
Publication status	Published - Jul 2022

Bibliographical note

Funding Information:
Disclosure: Dr. Hammerschlag has received support from the Children's Hospital Foundation and University of Queensland strategic funding. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munafò have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporación Postdoctoral Contract from Ministerio de Economía, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundström has received support from the Swedish Research Council (2017-02552). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Njølstad has received support from the European Research Council (AdG #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (54741), and the Norwegian Diabetes Association. Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611. Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystrøm has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Dr. Middeldorp has received support from the National Health and Medical Research Council, the University of Queensland, the Australian ADHD Professionals Association, and Clinical Excellence Queensland Queensland Health. She has served as associate editor of the American Journal of Medical Genetics Part B. Ms. Jami has received support from an Academy Ter Meulen grant from the Royal Netherlands Academy of Arts and Sciences. Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no602768. Drs. Allegrini, Benyamin, Diemer, Karhunen, Y. Lu, Q. Lu, Mishra, Nolte, Thiering, Zhou, Adkins, Ask, Chen, Ehli, Hakulinen, Hottenga, Korhonen, Mamun, Neumann, Rivadeneira, Silberg, van Beijsterveldt, Vuoksimaa, Tong, Burt, Harden, Harris, Hartman, Heinrich, Hypponen, Jarvelin, Keltikangas- Järvinen, Klump, Kuja-Halkola, Lehtimäki, Maes, Najman, Oldehinkel, Pennell, Snieder, Standl, Sunyer, Tiemeier, Williams, Messrs. Jiang, Mallard, Palviainen, and Mss. Tate, Wang, Henders, Marrington, and Whipp have reported no biomedical financial interests or potential conflicts of interest.

Funding Information:
The study was supported by the Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe (CAPICE) project. CAPICE has received funding from the European Union’s Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks, under grant agreement number 721567. Cohort-specific acknowledgements and funding information are described in Supplement 1 , available online. The summary statistics for the overall meta-analysis can be downloaded from the GWAS Catalog (Study Accession: GCST90054778). Other summary statistics are available from the corresponding author upon request.

Publisher Copyright:
© 2022 The Authors

Funding

Disclosure: Dr. Hammerschlag has received support from the Children's Hospital Foundation and University of Queensland strategic funding. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munafò have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporación Postdoctoral Contract from Ministerio de Economía, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundström has received support from the Swedish Research Council (2017-02552). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Njølstad has received support from the European Research Council (AdG #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (54741), and the Norwegian Diabetes Association. Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611. Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystrøm has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Dr. Middeldorp has received support from the National Health and Medical Research Council, the University of Queensland, the Australian ADHD Professionals Association, and Clinical Excellence Queensland Queensland Health. She has served as associate editor of the American Journal of Medical Genetics Part B. Ms. Jami has received support from an Academy Ter Meulen grant from the Royal Netherlands Academy of Arts and Sciences. Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no602768. Drs. Allegrini, Benyamin, Diemer, Karhunen, Y. Lu, Q. Lu, Mishra, Nolte, Thiering, Zhou, Adkins, Ask, Chen, Ehli, Hakulinen, Hottenga, Korhonen, Mamun, Neumann, Rivadeneira, Silberg, van Beijsterveldt, Vuoksimaa, Tong, Burt, Harden, Harris, Hartman, Heinrich, Hypponen, Jarvelin, Keltikangas- Järvinen, Klump, Kuja-Halkola, Lehtimäki, Maes, Najman, Oldehinkel, Pennell, Snieder, Standl, Sunyer, Tiemeier, Williams, Messrs. Jiang, Mallard, Palviainen, and Mss. Tate, Wang, Henders, Marrington, and Whipp have reported no biomedical financial interests or potential conflicts of interest. The study was supported by the Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe (CAPICE) project. CAPICE has received funding from the European Union’s Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks, under grant agreement number 721567. Cohort-specific acknowledgements and funding information are described in Supplement 1 , available online. The summary statistics for the overall meta-analysis can be downloaded from the GWAS Catalog (Study Accession: GCST90054778). Other summary statistics are available from the corresponding author upon request.

Funders	Funder number
Alcohol Research Center	R25 AA027402, U10 AA008401
Centro de Excelencia Severo Ochoa
Health Department of the Catalan Government
Health Research and Innovation Strategic Plan	SLT002/16/00201
MSCA-ITN-2016	721567
Nic Waals Institute
Personalized Medicine for Children and Adults
Koninklijke Nederlandse Akademie van Wetenschappen	HD093651, PAH/5535, R01 AA015416, MH117559, K02 AA018755, P50 AA022537
Shire/Takeda
de Catalunya
National Institutes of Health	K01MH113848, MH016880, MH100141, L30MH104939
National Institute on Alcohol Abuse and Alcoholism	DA032555, DA042755
Brain and Behavior Research Foundation	28632
Stiftelsen Kristian Gerhard Jebsen
National Alliance for Research on Schizophrenia and Depression	FJC2018-038085-I
“la Caixa” Foundation	LCF/PR/GN17/10300004
Horizon 2020 Framework Programme
Seventh Framework Programme	602768, 771057, 293574
Children's Hospital Foundation
European Molecular Biology Laboratory
Ministerio de Ciencia, Innovación y Universidades
HORIZON EUROPE Marie Sklodowska-Curie Actions
Medical Research Council
European Research Council
University of Bristol	MC_UU_00011/7
National Health and Medical Research Council	262177, 288083
Koninklijke Nederlandse Akademie van Wetenschappen
University of Queensland
ZonMw	531003014 937, 849200011
Academy of Finland	312073, 308248
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VI.Veni.191G.030
Jacobs Foundation
Vetenskapsrådet	2017-02552, 262700, 2016-1989
Seventh Framework Programme
Helse Vest Regionalt Helseføretak
Universitetet i Bergen	FRIPRO 240413
Norges forskningsråd	223273, 273291
Helse Sør-Øst RHF	2018059
Bergens Forskningsstiftelse
Forskningsrådet om Hälsa, Arbetsliv och Välfärd	2012-1678
Diabetesforbundet	DA03580, 274611, AA-000145, DA021905, G19/2
Novo Nordisk Fonden	54741
Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España	DA035804, DA011015, AG046938, DA044283, IJCI-2017-34068
Agencia Estatal de Investigación

Keywords

anxiety
depression
genetic epidemiology
molecular genetics
repeated measures

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https://linkinghub.elsevier.com/retrieve/pii/S0890856722001794

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Cite this

Jami, E. S., Hammerschlag, A. R., Ip, H. F., Allegrini, A. G., Benyamin, B., Border, R., Diemer, E. W., Jiang, C., Karhunen, V., Lu, Y., Lu, Q., Mallard, T. T., Mishra, P. P., Nolte, I. M., Palviainen, T., Peterson, R. E., Sallis, H. M., Shabalin, A. A., Tate, A. E., ... Middeldorp, C. M. (2022). Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 61(7), 934-945. https://doi.org/10.1016/j.jaac.2021.11.035

@article{69835f11f3cc43f1887b824739f089ab,

title = "Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms",

abstract = "Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.",

keywords = "anxiety, depression, genetic epidemiology, molecular genetics, repeated measures",

author = "Jami, {Eshim S.} and Hammerschlag, {Anke R.} and Ip, {Hill F.} and Allegrini, {Andrea G.} and Beben Benyamin and Richard Border and Diemer, {Elizabeth W.} and Chang Jiang and Ville Karhunen and Yi Lu and Qing Lu and Mallard, {Travis T.} and Mishra, {Pashupati P.} and Nolte, {Ilja M.} and Teemu Palviainen and Peterson, {Roseann E.} and Sallis, {Hannah M.} and Shabalin, {Andrey A.} and Tate, {Ashley E.} and Elisabeth Thiering and Nat{\`a}lia Vilor-Tejedor and Carol Wang and Ang Zhou and Adkins, {Daniel E.} and Silvia Alemany and Helga Ask and Qi Chen and Corley, {Robin P.} and Ehli, {Erik A.} and Evans, {Luke M.} and Alexandra Havdahl and Hagenbeek, {Fiona A.} and Christian Hakulinen and Henders, {Anjali K.} and Hottenga, {Jouke Jan} and Tellervo Korhonen and Abdullah Mamun and Shelby Marrington and Alexander Neumann and Kaili Rimfeld and Fernando Rivadeneira and Silberg, {Judy L.} and {van Beijsterveldt}, {Catharina E.} and Eero Vuoksimaa and Whipp, {Alyce M.} and Xiaoran Tong and Andreassen, {Ole A.} and Boomsma, {Dorret I.} and Brown, {Sandra A.} and Burt, {S. Alexandra} and William Copeland and Dick, {Danielle M.} and Harden, {K. Paige} and Harris, {Kathleen Mullan} and Hartman, {Catharina A.} and Joachim Heinrich and Hewitt, {John K.} and Christian Hopfer and Elina Hypponen and Jarvelin, {Marjo Riitta} and Jaakko Kaprio and Liisa Keltikangas-J{\"a}rvinen and Klump, {Kelly L.} and Kenneth Krauter and Ralf Kuja-Halkola and Henrik Larsson and Terho Lehtim{\"a}ki and Paul Lichtenstein and Sebastian Lundstr{\"o}m and Maes, {Hermine H.} and Per Magnus and Munaf{\`o}, {Marcus R.} and Najman, {Jake M.} and Nj{\o}lstad, {P{\aa}l R.} and Oldehinkel, {Albertine J.} and Pennell, {Craig E.} and Robert Plomin and Ted Reichborn-Kjennerud and Chandra Reynolds and Rose, {Richard J.} and Andrew Smolen and Harold Snieder and Michael Stallings and Marie Standl and Jordi Sunyer and Henning Tiemeier and Wadsworth, {Sally J.} and Wall, {Tamara L.} and Whitehouse, {Andrew J.O.} and Williams, {Gail M.} and Eivind Ystr{\o}m and Nivard, {Michel G.} and Meike Bartels and Middeldorp, {Christel M.}",

note = "Funding Information: Disclosure: Dr. Hammerschlag has received support from the Children's Hospital Foundation and University of Queensland strategic funding. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munaf{\`o} have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovaci{\'o}n y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporaci{\'o}n Postdoctoral Contract from Ministerio de Econom{\'i}a, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundstr{\"o}m has received support from the Swedish Research Council (2017-02552). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Nj{\o}lstad has received support from the European Research Council (AdG #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (54741), and the Norwegian Diabetes Association. Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611. Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystr{\o}m has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Dr. Middeldorp has received support from the National Health and Medical Research Council, the University of Queensland, the Australian ADHD Professionals Association, and Clinical Excellence Queensland Queensland Health. She has served as associate editor of the American Journal of Medical Genetics Part B. Ms. Jami has received support from an Academy Ter Meulen grant from the Royal Netherlands Academy of Arts and Sciences. Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no602768. Drs. Allegrini, Benyamin, Diemer, Karhunen, Y. Lu, Q. Lu, Mishra, Nolte, Thiering, Zhou, Adkins, Ask, Chen, Ehli, Hakulinen, Hottenga, Korhonen, Mamun, Neumann, Rivadeneira, Silberg, van Beijsterveldt, Vuoksimaa, Tong, Burt, Harden, Harris, Hartman, Heinrich, Hypponen, Jarvelin, Keltikangas- J{\"a}rvinen, Klump, Kuja-Halkola, Lehtim{\"a}ki, Maes, Najman, Oldehinkel, Pennell, Snieder, Standl, Sunyer, Tiemeier, Williams, Messrs. Jiang, Mallard, Palviainen, and Mss. Tate, Wang, Henders, Marrington, and Whipp have reported no biomedical financial interests or potential conflicts of interest. Funding Information: The study was supported by the Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe (CAPICE) project. CAPICE has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks, under grant agreement number 721567. Cohort-specific acknowledgements and funding information are described in Supplement 1 , available online. The summary statistics for the overall meta-analysis can be downloaded from the GWAS Catalog (Study Accession: GCST90054778). Other summary statistics are available from the corresponding author upon request. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jul,

doi = "10.1016/j.jaac.2021.11.035",

language = "English",

volume = "61",

pages = "934--945",

journal = "Journal of the American Academy of Child and Adolescent Psychiatry",

issn = "0890-8567",

publisher = "Elsevier Limited",

number = "7",

}

Jami, ES, Hammerschlag, AR, Ip, HF, Allegrini, AG, Benyamin, B, Border, R, Diemer, EW, Jiang, C, Karhunen, V, Lu, Y, Lu, Q, Mallard, TT, Mishra, PP, Nolte, IM, Palviainen, T, Peterson, RE, Sallis, HM, Shabalin, AA, Tate, AE, Thiering, E, Vilor-Tejedor, N, Wang, C, Zhou, A, Adkins, DE, Alemany, S, Ask, H, Chen, Q, Corley, RP, Ehli, EA, Evans, LM, Havdahl, A, Hagenbeek, FA, Hakulinen, C, Henders, AK, Hottenga, JJ, Korhonen, T, Mamun, A, Marrington, S, Neumann, A, Rimfeld, K, Rivadeneira, F, Silberg, JL, van Beijsterveldt, CE, Vuoksimaa, E, Whipp, AM, Tong, X, Andreassen, OA, Boomsma, DI, Brown, SA, Burt, SA, Copeland, W, Dick, DM, Harden, KP, Harris, KM, Hartman, CA, Heinrich, J, Hewitt, JK, Hopfer, C, Hypponen, E, Jarvelin, MR, Kaprio, J, Keltikangas-Järvinen, L, Klump, KL, Krauter, K, Kuja-Halkola, R, Larsson, H, Lehtimäki, T, Lichtenstein, P, Lundström, S, Maes, HH, Magnus, P, Munafò, MR, Najman, JM, Njølstad, PR, Oldehinkel, AJ, Pennell, CE, Plomin, R, Reichborn-Kjennerud, T, Reynolds, C, Rose, RJ, Smolen, A, Snieder, H, Stallings, M, Standl, M, Sunyer, J, Tiemeier, H, Wadsworth, SJ, Wall, TL, Whitehouse, AJO, Williams, GM, Ystrøm, E, Nivard, MG , Bartels, M & Middeldorp, CM 2022, 'Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms', Journal of the American Academy of Child and Adolescent Psychiatry, vol. 61, no. 7, pp. 934-945. https://doi.org/10.1016/j.jaac.2021.11.035

TY - JOUR

T1 - Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

AU - Jami, Eshim S.

AU - Hammerschlag, Anke R.

AU - Ip, Hill F.

AU - Allegrini, Andrea G.

AU - Benyamin, Beben

AU - Border, Richard

AU - Diemer, Elizabeth W.

AU - Jiang, Chang

AU - Karhunen, Ville

AU - Lu, Yi

AU - Lu, Qing

AU - Mallard, Travis T.

AU - Mishra, Pashupati P.

AU - Nolte, Ilja M.

AU - Palviainen, Teemu

AU - Peterson, Roseann E.

AU - Sallis, Hannah M.

AU - Shabalin, Andrey A.

AU - Tate, Ashley E.

AU - Thiering, Elisabeth

AU - Vilor-Tejedor, Natàlia

AU - Wang, Carol

AU - Zhou, Ang

AU - Adkins, Daniel E.

AU - Alemany, Silvia

AU - Ask, Helga

AU - Chen, Qi

AU - Corley, Robin P.

AU - Ehli, Erik A.

AU - Evans, Luke M.

AU - Havdahl, Alexandra

AU - Hagenbeek, Fiona A.

AU - Hakulinen, Christian

AU - Henders, Anjali K.

AU - Hottenga, Jouke Jan

AU - Korhonen, Tellervo

AU - Mamun, Abdullah

AU - Marrington, Shelby

AU - Neumann, Alexander

AU - Rimfeld, Kaili

AU - Rivadeneira, Fernando

AU - Silberg, Judy L.

AU - van Beijsterveldt, Catharina E.

AU - Vuoksimaa, Eero

AU - Whipp, Alyce M.

AU - Tong, Xiaoran

AU - Andreassen, Ole A.

AU - Boomsma, Dorret I.

AU - Brown, Sandra A.

AU - Burt, S. Alexandra

AU - Copeland, William

AU - Dick, Danielle M.

AU - Harden, K. Paige

AU - Harris, Kathleen Mullan

AU - Hartman, Catharina A.

AU - Heinrich, Joachim

AU - Hewitt, John K.

AU - Hopfer, Christian

AU - Hypponen, Elina

AU - Jarvelin, Marjo Riitta

AU - Kaprio, Jaakko

AU - Keltikangas-Järvinen, Liisa

AU - Klump, Kelly L.

AU - Krauter, Kenneth

AU - Kuja-Halkola, Ralf

AU - Larsson, Henrik

AU - Lehtimäki, Terho

AU - Lichtenstein, Paul

AU - Lundström, Sebastian

AU - Maes, Hermine H.

AU - Magnus, Per

AU - Munafò, Marcus R.

AU - Najman, Jake M.

AU - Njølstad, Pål R.

AU - Oldehinkel, Albertine J.

AU - Pennell, Craig E.

AU - Plomin, Robert

AU - Reichborn-Kjennerud, Ted

AU - Reynolds, Chandra

AU - Rose, Richard J.

AU - Smolen, Andrew

AU - Snieder, Harold

AU - Stallings, Michael

AU - Standl, Marie

AU - Sunyer, Jordi

AU - Tiemeier, Henning

AU - Wadsworth, Sally J.

AU - Wall, Tamara L.

AU - Whitehouse, Andrew J.O.

AU - Williams, Gail M.

AU - Ystrøm, Eivind

AU - Nivard, Michel G.

AU - Bartels, Meike

AU - Middeldorp, Christel M.

N1 - Funding Information: Disclosure: Dr. Hammerschlag has received support from the Children's Hospital Foundation and University of Queensland strategic funding. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munafò have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporación Postdoctoral Contract from Ministerio de Economía, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundström has received support from the Swedish Research Council (2017-02552). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Njølstad has received support from the European Research Council (AdG #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (54741), and the Norwegian Diabetes Association. Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611. Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystrøm has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Dr. Middeldorp has received support from the National Health and Medical Research Council, the University of Queensland, the Australian ADHD Professionals Association, and Clinical Excellence Queensland Queensland Health. She has served as associate editor of the American Journal of Medical Genetics Part B. Ms. Jami has received support from an Academy Ter Meulen grant from the Royal Netherlands Academy of Arts and Sciences. Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no602768. Drs. Allegrini, Benyamin, Diemer, Karhunen, Y. Lu, Q. Lu, Mishra, Nolte, Thiering, Zhou, Adkins, Ask, Chen, Ehli, Hakulinen, Hottenga, Korhonen, Mamun, Neumann, Rivadeneira, Silberg, van Beijsterveldt, Vuoksimaa, Tong, Burt, Harden, Harris, Hartman, Heinrich, Hypponen, Jarvelin, Keltikangas- Järvinen, Klump, Kuja-Halkola, Lehtimäki, Maes, Najman, Oldehinkel, Pennell, Snieder, Standl, Sunyer, Tiemeier, Williams, Messrs. Jiang, Mallard, Palviainen, and Mss. Tate, Wang, Henders, Marrington, and Whipp have reported no biomedical financial interests or potential conflicts of interest. Funding Information: The study was supported by the Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe (CAPICE) project. CAPICE has received funding from the European Union’s Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks, under grant agreement number 721567. Cohort-specific acknowledgements and funding information are described in Supplement 1 , available online. The summary statistics for the overall meta-analysis can be downloaded from the GWAS Catalog (Study Accession: GCST90054778). Other summary statistics are available from the corresponding author upon request. Publisher Copyright: © 2022 The Authors

PY - 2022/7

Y1 - 2022/7

N2 - Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

AB - Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

KW - anxiety

KW - depression

KW - genetic epidemiology

KW - molecular genetics

KW - repeated measures

UR - http://www.scopus.com/inward/record.url?scp=85128378571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85128378571&partnerID=8YFLogxK

U2 - 10.1016/j.jaac.2021.11.035

DO - 10.1016/j.jaac.2021.11.035

M3 - Article

C2 - 35378236

SN - 0890-8567

VL - 61

SP - 934

EP - 945

JO - Journal of the American Academy of Child and Adolescent Psychiatry

JF - Journal of the American Academy of Child and Adolescent Psychiatry

IS - 7

ER -

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

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