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Type: Journal article
Title: A genome-wide association meta-analysis of preschool internalizing problems
Author: Benke, K.
Nivard, M.
Velders, F.
Walters, R.
Pappa, I.
Scheet, P.
Xiao, X.
Ehli, E.
Palmer, L.
Whitehouse, A.
Verhulst, F.
Jaddoe, V.
Rivadeneira, F.
Groen-Blokhuis, M.
Van Beijsterveldt, C.
Davies, G.
Hudziak, J.
Lubke, G.
Boomsma, D.
Pennell, C.
et al.
Citation: Journal of the American Academy of Child and Adolescent Psychiatry, 2014; 53(6):667-676.e7
Publisher: Elsevier
Issue Date: 2014
ISSN: 0890-8567
Statement of
Kelly S. Benke, Michel G. Nivard, Fleur P. Velders, Raymond K. Walters, Irene Pappa, Paul A. Scheet, Xiangjun Xiao, Erik A. Ehli, Lyle J. Palmer, Andrew J.O. Whitehouse, Frank C. Verhulst, Vincent W. Jaddoe, Fernando Rivadeneira, Maria M. Groen-Blokhuis, Catharina E.M. van Beijsterveldt, Gareth E. Davies, James J. Hudziak, Gitta H. Lubke, Dorret I. Boomsma, Craig E. Pennell, Henning Tiemeier, Christel M. Middeldorp, for the Early Genetics and Lifecourse Epidemiology Consortium
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.
Keywords: GWA study; internalizing problems; pcsk2; variance explained; GCTA
Rights: Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaac.2013.12.028
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