Genome-wide association study of alcohol dependence.
BACKGROUND
Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.


OBJECTIVE
To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.


METHODS
The GWAS tested 524,396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10(-4) were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.


METHODS
Five university hospitals in southern and central Germany.


METHODS
The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.


METHODS
Significant association findings in the GWAS and follow-up study with the same alleles.


RESULTS
The GWAS produced 121 SNPs with nominal P < 10(-4). These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10(-9); rs1344694, P = 1.69 x 10(-8)). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.


CONCLUSIONS
This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.
Treutlein
Jens
J
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
Cichon
Sven
S
Ridinger
Monika
M
Wodarz
Norbert
N
Soyka
Michael
M
Zill
Peter
P
Maier
Wolfgang
W
Moessner
Rainald
R
Gaebel
Wolfgang
W
Dahmen
Norbert
N
Fehr
Christoph
C
Scherbaum
Norbert
N
Steffens
Michael
M
Ludwig
Kerstin U
KU
Frank
Josef
J
Wichmann
H Erich
HE
Schreiber
Stefan
S
Dragano
Nico
N
Sommer
Wolfgang H
WH
Leonardi-Essmann
Fernando
F
Lourdusamy
Anbarasu
A
Gebicke-Haerter
Peter
P
Wienker
Thomas F
TF
Sullivan
Patrick F
PF
Nöthen
Markus M
MM
Kiefer
Falk
F
Spanagel
Rainer
R
Mann
Karl
K
Rietschel
Marcella
M
D000328:Adult; D017668:Age of Onset; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000430:Alcohol Withdrawal Delirium / Q000235:genetics / Q000534:rehabilitation; D000437:Alcoholism / Q000235:genetics* / Q000534:rehabilitation; D000483:Alleles; D000679:Amygdala / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000235:genetics; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000473:pathology; D002889:Chromosomes, Human, Pair 2; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006760:Hospitalization; D006801:Humans; D008126:Lod Score; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011699:Putamen / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D055815:Young Adult
D015820:Cadherins; D005819:Genetic Markers; C099972:H-cadherin; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase