A Genome-wide Association Meta-analysis of Preschool Internalizing Problems

K.S. Benke, M.G. Nivard, F.P. Velders, R.K. Walters, I. Pappa, P. Scheet, X. Xiao, E.A. Ehli, L.J. Palmer, A.J.O. Whitehouse, F.C. Verhulst, V.W. Jaddoe, F. Rivadeneira, M.M. Blokhuis, C.E.M. van Beijsterveldt, G.E. Davies, J.J. Hudziak, G.H. Lubke, D.I. Boomsma, C.E. PennellH. Tiemeier, C.M. Middeldorp

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Objective Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL). Method First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT. Results Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p <.03). Conclusion Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders.
Original languageEnglish
Pages (from-to)667-676
Number of pages10
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Volume53
Issue number6
DOIs
Publication statusPublished - 2014

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