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Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

By 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, Ashley E Tate, Elisabeth Thiering, Natàlia Vilor-Tejedor, Carol Wang, Ang Zhou, Daniel E Adkins, Silvia Alemany, Helga Ask, Qi Chen, Robin P. Corley, Gareth E. Davies, 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, Andrey A. Shabalin, Judy L Silberg, Catharina E van Beijsterveldt, Eero Vuoksimaa, Alyce M Whipp, Tong Xiaoran, Ole A. Andreassen, Dorret Boomsma, Sandra A. Brown, S Alexandra Burt, William Copeland, Elizabeth J Costello, Danielle M Dick, Lindon J. Eaves, 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 Lehtimaki, Paul Lichtenstein, Sebastian Lundstrom, 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 Sneider, Michael Stallings, Marie Standl, Jordi Sunyer, Henning Tiemeier, Sally Wadsworth, Tamara L. Wall, Andrew J O Whitehouse, Gail M Williams, Eivind Ystrom, Michel G Nivard, Meike Bartels, Christel M Middeldorp

Posted 13 Sep 2020
medRxiv DOI: 10.1101/2020.09.11.20175026

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses showed rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Gene-based analyses showed significant associations with three genes: WNT3 (p=1.13x10-06), CCL26 (p=1.88x10-06), and CENPO (p=2.54x10-06). Of these, WNT3 was previously associated with neuroticism, with which INToverall also shared a strong genetic correlation (rg=0.76). Genetic correlations were also 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. Overall, childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could explain both the persistence of internalising 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.

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