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; Marcus R. Munafò

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, Marcus R. Munafò

Vice Chancellor's Office

Vrije Universiteit Amsterdam
University College London
Amsterdam Public Health
University of Queensland
King's College London
University of South Australia
South Australian Health and Medical Research Institute
University of Colorado
Erasmus University Medical Center
Harvard University
Michigan State University
University of Florida
Imperial College London
The Karolinska Institute
University of Texas
Tampere University of Technology
Rijksuniversiteit Groningen
University of Helsinki
Virginia Institute for Psychiatric and Behavioral Genetics
University of Bristol
University of Utah
Helmholtz Center Munich - German Research Center for Environmental Health
Ludwig Maximilian University of Munich
Universitat Pompeu Fabra
Barcelona Institute of Science and Technology
The University of Newcastle, Australia
University of Barcelona
Norwegian Institute of Public Health
Avera McKennan Hospital & University Health Center
Jewish General Hospital
University of Oslo
University of California, San Diego
School of Psychological Science
University Hospitals Bristol NHS Foundation Trust

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

49 Citations (SciVal)

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	31 Mar 2022
DOIs	https://doi.org/10.1016/j.jaac.2021.11.035
Publication status	Published - 31 Jul 2022

Acknowledgements

The authors extend a warm thank you to all participants, their parents, and teachers for taking part in this study. They would also like to thank Gareth E. Davies, PhD, of the University of South Dakota, Elizabeth J. Costello, PhD, of Duke University, and Lindon J. Eaves, PhD, of Virginia Commonwealth University, for their input on earlier versions of this manuscript.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

anxiety
depression
genetic epidemiology
molecular genetics
repeated measures

ASJC Scopus subject areas

Developmental and Educational Psychology
Psychiatry and Mental health

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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., ... Munafò, M. R. (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

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 & Munafò, MR 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

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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 Munaf{\`o}, \{Marcus R.\}",

year = "2022",

month = jul,

day = "31",

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",

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publisher = "Elsevier",

number = "7",

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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 - Munafò, Marcus R.

PY - 2022/7/31

Y1 - 2022/7/31

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

Abstract

Acknowledgements

UN SDGs

Keywords

ASJC Scopus subject areas

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