Genome-wide Association Study of Alcohol Dependence

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
Archives of general psychiatry (Impact Factor: 14.48). 08/2009; 66(7):773-84. DOI: 10.1001/archgenpsychiatry.2009.83
Source: PubMed


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.
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.
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.
Five university hospitals in southern and central Germany.
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.
Significant association findings in the GWAS and follow-up study with the same alleles.
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.
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.

84 Reads
    • "Cadherin-13 expression has been detected, among others, in dopamine neurons in ventral tegmental area, substantia nigra, and locus coeruleus, and as such had been implicated in ADHD and co-morbid disorders including SUDs (Rivero et al. 2013). Indeed, the CDH13 gene has been implicated in several genome-wide association studies of ADHD (Franke, Neale & Faraone 2009) and SUDs (Uhl et al. 2008; Treutlein et al. 2009). Another possible candidate is the NOS1 gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders. © 2015 Society for the Study of Addiction.
    Addiction Biology 04/2015; DOI:10.1111/adb.12230 · 5.36 Impact Factor
  • Source
    • "Susceptibility loci have been mapped to various chromosomes using genetic linkage methods [Reich et al., 1998; Williams et al., 1999b; Foroud et al., 2000; Nurnberger et al., 2001; Dick et al., 2002; Prescott et al., 2006; Gelernter et al., 2009], with successful gene localization occurring from the follow-up of some positive linkage regions, most notably GABRA2 and ADH4 [Edenberg et al., 2004, 2006a]. More recently, the first generation of genome-wide, case–control association studies (GWAS) revealed a number of promising SNP associations to AUD [Treutlein et al., 2009; Bierut et al., 2010; Edenberg et al., 2010; Gelernter et al., 2014], although most of the variation in genetic liability remains to be explained. Genetic analyses of alcoholism have tended to rely on binary measures of dependence, despite the continuum of alcohol-related problems that underlie its symptomatology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2) = 0.32 ± 0.05; P = 4.61 × 10(-14) ) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10(-6) ) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10(-3) ), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10(-4) ), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32231 · 3.42 Impact Factor
  • Source
    • "duals of European origin or ancestry have produced conflicting results ( Macgregor et al . 2009 ; Edenberg et al . 2010 ; Frank et al . 2012 ) . Thus , in one GWAS , rs1789891 showed nominal but not genome - wide significance with ADS ( Edenberg et al . 2010 ) , while no significant association was found in the other two ( Macgregor et al . 2009 ; Bierut et al . 2010 ) . Further , con - ditional analysis of the German GWAS data indicated that partly independent signals from other markers also contributed to the observed associations supporting the role of other variants in the ADH gene cluster affecting ADS risk ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10−6, odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10−5, OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.
    Addiction Biology 05/2014; 20(3). DOI:10.1111/adb.12141 · 5.36 Impact Factor
Show more