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Multicenter Study
. 2009 Jul;66(7):773-84.
doi: 10.1001/archgenpsychiatry.2009.83.

Genome-wide association study of alcohol dependence

Jens Treutlein  1 , Sven Cichon, Monika Ridinger, Norbert Wodarz, Michael Soyka, Peter Zill, Wolfgang Maier, Rainald Moessner, Wolfgang Gaebel, Norbert Dahmen, Christoph Fehr, Norbert Scherbaum, Michael Steffens, Kerstin U Ludwig, Josef Frank, H Erich Wichmann, Stefan Schreiber, Nico Dragano, Wolfgang H Sommer, Fernando Leonardi-Essmann, Anbarasu Lourdusamy, Peter Gebicke-Haerter, Thomas F Wienker, Patrick F Sullivan, Markus M Nöthen, Falk Kiefer, Rainer Spanagel, Karl Mann, Marcella Rietschel
Affiliations
Multicenter Study

Genome-wide association study of alcohol dependence

Jens Treutlein et al. Arch Gen Psychiatry. 2009 Jul.

Abstract

Context: 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.

Design: 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.

Setting: Five university hospitals in southern and central Germany.

Participants: 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.

Main outcome measures: 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.

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Figures

Figure 1
Figure 1
Pre and post quality control QQ plot of Armitage's trend test p-values of autosomal SNPs. SNPs at which the test statistic exceeds 30, are represented by triangles at the top of the plot.
Figure 2
Figure 2
Genome-wide overview of GWAS findings. SNPs at which the test statistic exceeds 30, are represented by triangles at the top of the plot.
Figure 3
Figure 3
Illustration of p-values in a +/− 1Mb interval around the most significant findings at 2q35: rs1344694, rs7590720 and rs705648. Gene annotations from UCSC RefSeq genes, LD-maps from HapMap.
Figure 4
Figure 4
Illustration of p-values in a +/− 1Mb interval around the most significant finding rs1864982 at 5q32.Gene annotations from UCSC RefSeq genes, LD-maps from HapMap.
Figure 5
Figure 5
Illustration of p-values in a +/− 1Mb interval around the most significant finding rs12388359 at Xp22.2. Gene annotations from UCSC RefSeq genes, LD-maps from HapMap.
See this image and copyright information in PMC

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