Genome-wide association study in German patients with attention deficit/hyperactivity disorder.
The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. anke.hinney@uni-due.de
Anke
A
Hinney
André
A
Scherag
Ivonne
I
Jarick
Özgür
Ö
Albayrak
Carolin
C
Pütter
Sonali
S
Pechlivanis
Maria R
MR
Dauvermann
Sebastian
S
Beck
Heike
H
Weber
Susann
S
Scherag
Trang T
TT
Nguyen
Anna-Lena
AL
Volckmar
Nadja
N
Knoll
Stephen V
SV
Faraone
Benjamin M
BM
Neale
Barbara
B
Franke
Sven
S
Cichon
Per
P
Hoffmann
Markus M
MM
Nöthen
Stefan
S
Schreiber
Karl-Heinz
KH
Jöckel
H-Erich
HE
Wichmann
Christine
C
Freitag
Thomas
T
Lempp
Jobst
J
Meyer
Susanne
S
Gilsbach
Beate
B
Herpertz-Dahlmann
Judith
J
Sinzig
Gerd
G
Lehmkuhl
Tobias J
TJ
Renner
Andreas
A
Warnke
Marcel
M
Romanos
Klaus-Peter
KP
Lesch
Andreas
A
Reif
Benno G
BG
Schimmelmann
Johannes
J
Hebebrand
D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002648:Child; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics
C578935:GRM5 protein, human; D005819:Genetic Markers; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate