Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder.
OBJECTIVE
Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power.


METHODS
We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis.


RESULTS
No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder.


CONCLUSIONS
Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.
Neale
Benjamin M
BM
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
Medland
Sarah E
SE
Ripke
Stephan
S
Asherson
Philip
P
Franke
Barbara
B
Lesch
Klaus-Peter
KP
Faraone
Stephen V
SV
Nguyen
Thuy Trang
TT
Schäfer
Helmut
H
Holmans
Peter
P
Daly
Mark
M
Steinhausen
Hans-Christoph
HC
Freitag
Christine
C
Reif
Andreas
A
Renner
Tobias J
TJ
Romanos
Marcel
M
Romanos
Jasmin
J
Walitza
Susanne
S
Warnke
Andreas
A
Meyer
Jobst
J
Palmason
Haukur
H
Buitelaar
Jan
J
Vasquez
Alejandro Arias
AA
Lambregts-Rommelse
Nanda
N
Gill
Michael
M
Anney
Richard J L
RJ
Langely
Kate
K
O'Donovan
Michael
M
Williams
Nigel
N
Owen
Michael
M
Thapar
Anita
A
Kent
Lindsey
L
Sergeant
Joseph
J
Roeyers
Herbert
H
Mick
Eric
E
Biederman
Joseph
J
Doyle
Alysa
A
Smalley
Susan
S
Loo
Sandra
S
Hakonarson
Hakon
H
Elia
Josephine
J
Todorov
Alexandre
A
Miranda
Ana
A
Mulas
Fernando
F
Ebstein
Richard P
RP
Rothenberger
Aribert
A
Banaschewski
Tobias
T
Oades
Robert D
RD
Sonuga-Barke
Edmund
E
McGough
James
J
Nisenbaum
Laura
L
Middleton
Frank
F
Hu
Xiaolan
X
Nelson
Stan
S
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics