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, Tong Xiaoran, 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 journalArticleAcademicpeer-review

8 Citations (Scopus)
10 Downloads (Pure)


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 aged between 3 and 18. 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 polymorphisms (SNP) heritability (1.66%, 95% confidence intervals 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% confidence intervals 3.08-8.18%). Additive genetic effects on internalizing symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing 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 amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Original languageEnglish
Pages (from-to)934-945
Number of pages12
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Issue number7
Early online date1-Apr-2022
Publication statusPublished - Jul-2022

Cite this