Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 36, Issue 12, Pages 2086-2094Publisher
WILEY
DOI: 10.1111/j.1530-0277.2012.01843.x
Keywords
Alcohol Dependence; Candidate Genes; Genome-Wide Association Studies; Genetics
Categories
Funding
- National Institute on Drug Abuse [K02 DA021237, R01 DA013423, R01 DA019963]
- GENEVA Coordinating Center from the National Human Genome Research Institute [U01 HG004446]
- National Cancer Institute [P01 CA089392]
- National Institute on Alcohol Abuse and Alcoholism [U10 AA008401]
- NIH GEI [U01HG004438]
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse
- NIH [HHSN268200782096C]
- National Research Service Award Medical Scientist Training Grant from the National Institute of General Medical Sciences [T32 GM007200]
- [U01 HG004422]
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Background Genome-wide association (GWA) studies have led to a paradigm shift in how researchers study the genetics underlying disease. Many GWA studies are now publicly available and can be used to examine whether or not previously proposed candidate genes are supported by GWA data. This approach is particularly important for the field of alcoholism because the contribution of many candidate genes remains controversial. Methods Using the Human Genome Epidemiology (HuGE) Navigator, we selected candidate genes for alcoholism that have been frequently examined in scientific articles in the past decade. Specific candidate loci as well as all the reported single nucleotide polymorphisms (SNPs) in candidate genes were examined in the Study of Addiction: Genetics and Environment (SAGE), a GWA study comparing alcohol-dependent and nondependent subjects. Results Several commonly reported candidate loci, including rs1800497 in DRD2, rs698 in ADH1C, rs1799971 in OPRM1, and rs4680 in COMT, are not replicated in SAGE (p > 0.05). Among candidate loci available for analysis, only rs279858 in GABRA2 (p = 0.0052, OR = 1.16) demonstrated a modest association. Examination of all SNPs reported in SAGE in over 50 candidate genes revealed no SNPs with large frequency differences between cases and controls, and the lowest p-value of any SNP was 0.0006. Conclusions We provide evidence that several extensively studied candidate loci do not have a strong contribution to risk of developing alcohol dependence in European and African ancestry populations. Owing to the lack of coverage, we were unable to rule out the contribution of other variants, and these genes and particular loci warrant further investigation. Our analysis demonstrates that publicly available GWA results can be used to better understand which if any of previously proposed candidate genes contribute to disease. Furthermore, we illustrate how examining the convergence of candidate gene and GWA studies can help elucidate the genetic architecture of alcoholism and more generally complex diseases.
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