A genome-wide association meta-analysis of preschool internalizing problems.
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).


METHODS
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).


CONCLUSIONS
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.
Johns Hopkins Bloomberg School of Public Health, Baltimore, USA and the Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Canada. Electronic address: kbenke@jhsph.edu.
Kelly S
KS
Benke
VU University Amsterdam, The Netherlands and the Neuroscience Campus Amsterdam, VU University.
Michel G
MG
Nivard
Erasmus Medical Center, Rotterdam, The Netherlands and The Generation R Study Group, Erasmus Medical Center.
Fleur P
FP
Velders
University of Notre Dame, Notre Dame, USA.
Raymond K
RK
Walters
School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, the Generation R Study Group, and Erasmus University Medical Center-Sophia Children's Hospital.
Irene
I
Pappa
University of Texas / M. D. Anderson Cancer Center, USA.
Paul A
PA
Scheet
University of Texas / M. D. Anderson Cancer Center.
Xiangjun
X
Xiao
Avera Institute for Human Genetics, Sioux Falls, SD, USA.
Erik A
EA
Ehli
Samuel Lunenfeld Research Institute, University of Toronto, and the Ontario Institute for Cancer Research, Toronto, Canada.
Lyle J
LJ
Palmer
Telethon Institute for Child Health Research, Subiaco, Australia, The Centre for Child Health Research, The University of Western Australia, Perth and the School of Psychology, The University of Western Australia, Crawley.
Andrew J O
AJ
Whitehouse
Erasmus Medical Center.
Frank C
FC
Verhulst
Erasmus Medical Center, and The Generation R Study Group.
Vincent W
VW
Jaddoe
Erasmus Medical Center.
Fernando
F
Rivadeneira
VU University Amsterdam and EMGO+ Institute for Health and Care Research, VU University Medical Center.
Maria M
MM
Groen-Blokhuis
VU University Amsterdam.
Catharina E M
CE
van Beijsterveldt
Avera Institute for Human Genetics.
Gareth E
GE
Davies
Vermont Center for Children, Youth, and Families, and the University of Vermont, College of Medicine, Vermont, USA.
James J
JJ
Hudziak
University of Notre Dame and with VU University Amsterdam.
Gitta H
GH
Lubke
Neuroscience Campus Amsterdam, VU University Amsterdam, and EMGO+ Institute for Health and Care Research, VU University Medical Center.
Dorret I
DI
Boomsma
School of Women's and Infants' Health, The University of Western Australia.
Craig E
CE
Pennell
Erasmus Medical Center.
Henning
H
Tiemeier
Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/ VU University Medical Center.
Christel M
CM
Middeldorp
D002653:Child Behavior Disorders / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D045706:Proprotein Convertase 2 / Q000235:genetics*; D012042:Registries / Q000706:statistics & numerical data*
C581329:PCSK2 protein, human; D045706:Proprotein Convertase 2
GCTA; GWA study; internalizing problems; pcsk2; variance explained