A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications
Heath, Andrew C., Whitfield, John B., Martin, Nicholas G., Pergadia, Michele L., Goate, Alison M., Lind, Penelope A., McEvoy, Brian P., Schrage, Andrew J., Grant, Julia D., Chou, Yi-Ling, Zhu, Rachel, Henders, Anjali K., Medland, Sarah E., Gordon, Scott D., Nelson, Elliot C., Agrawal, Arpana, Nyholt, Dale R., Bucholz, Kathleen K., Madden, Pamela A.F., & Montgomery, Grant W. (2011) A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biological Psychiatry, 70(6), pp. 513-518.
Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence.
Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data.
No findings reached genome-wide significance (p = 8.4 x 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 x 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk.
We conclude that:
1) meta-analyses of consumption data may contribute usefully to gene discovery;
2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging, and;
3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).
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|Item Type:||Journal Article|
|Keywords:||Alcohol Drinking/*genetics, Alcoholism/diagnosis/*genetics, Case-Control Studies, Genetic Predisposition to Disease/*genetics, Genome-Wide Association Study/*statistics & numerical data, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci/*genetics, Residence Characteristics|
|Deposited On:||14 Jan 2016 22:55|
|Last Modified:||20 Jan 2016 05:40|
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