Common biological networks underlie genetic risk for alcoholism in African‐ and European‐American populations

Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome‐wide association studies (GWAS) account for only a...

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Published in:	Genes, brain and behavior Vol. 12; no. 5; pp. 532 - 542
Main Authors:	Kos, M. Z., Yan, J., Dick, D. M., Agrawal, A., Bucholz, K. K., Rice, J. P., Johnson, E. O., Schuckit, M., Kuperman, S., Kramer, J., Goate, A. M., Tischfield, J. A., Foroud, T., Nurnberger, J., Hesselbrock, V., Porjesz, B., Bierut, L. J., Edenberg, H. J., Almasy, L.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-07-2013 Blackwell John Wiley & Sons, Inc
Subjects:	Addiction Addictive behaviors Adult Adult and adolescent clinical studies Alcohol dependence Alcoholism Alcoholism - ethnology Alcoholism - genetics Alcoholism and acute alcohol poisoning Biological and medical sciences Black or African American - genetics Female Gene Regulatory Networks Genetic Predisposition to Disease Genome-Wide Association Study GWAS Humans Male Medical sciences pathway analysis polymarker scores Polymorphism, Genetic Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry rare variants synthetic association Toxicology United States White People - genetics United States Human rare variants GWAS Alcoholism Genetic variant synthetic association Alcohol dependence pathway analysis Genetic determinism Biological network Ethnic group Alcoholic beverage polymarker scores Association Analysis Dependence Risk factor Genetics Caucasoid African American
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Summary:	Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome‐wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome‐wide SNPs collectively account for risk of AD in two US populations, African‐Americans (AAs) and European‐Americans (EAs). Analyzing GWAS data for two independent case–control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10–3 and 2.08 × 10–4 for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF < 0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs. Figure 4: Significant genetic enrichment was observed at various P‐value thresholds for EA and AA GWAS data.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1601-1848 1601-183X 1601-183X
DOI:	10.1111/gbb.12043