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 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

^*Corresponding author for this work

Vrije Universiteit Amsterdam
University College London
Amsterdam UMC
University of Queensland
King's College London
Adelaide University
South Australian Health And Medical Research Institute
University of Colorado Boulder
Erasmus University Rotterdam
Harvard University
Michigan State University
University of Florida
Imperial College London
Karolinska Institutet
University of Texas at Austin
Tampere University
University of Groningen
University of Helsinki
Virginia Commonwealth University
University of Bristol
University of Utah
Helmholtz Zentrum München - German Research Center for Environmental Health
Ludwig Maximilian University of Munich
Centre for Genomic Regulation
Pompeu Fabra University
University of Newcastle
Barcelona Institute for Global Health
Norwegian Institute of Public Health
Avera Health
Sir Mortimer B. Davis-Jewish General Hospital
University of Oslo
University of California at San Diego
University of Vermont
University of North Carolina at Chapel Hill
University of Melbourne
University of Colorado Anschutz Medical Campus
University of Oulu
University of Gothenburg
University Hospitals Bristol and Weston NHS Foundation Trust
University of Bergen
University of California at Riverside
Hospital del Mar
Telethon Kids Institute
Children’s Health Queensland

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

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
DOIs	https://doi.org/10.1016/j.jaac.2021.11.035
Publication status	Published - Jul 2022
Externally published	Yes

Keywords

anxiety
depression
genetic epidemiology
molecular genetics
repeated measures

Access to Document

10.1016/j.jaac.2021.11.035

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{1b51cc13f4b247a7b816e45e3b845451,

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 = "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 Inc.",

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.

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 - https://www.scopus.com/pages/publications/85128378571

U2 - 10.1016/j.jaac.2021.11.035

DO - 10.1016/j.jaac.2021.11.035

M3 - Article

C2 - 35378236

AN - SCOPUS:85128378571

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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