The Aggregate Effect of Dopamine Genes on Dependence Symptoms Among Cocaine Users: Cross-Validation of a Candidate System Scoring Approach

Behavior Genetics - 2012
Jaime Derringer1, Robert F. Krueger2, Danielle M. Dick3, Fazil Aliev3,4, Richard A. Grucza5, Scott Saccone5, Arpana Agrawal5, Howard J. Edenberg6, Alison M. Goate5, Victor M. Hesselbrock7, John R. Kramer8, Peng Lin5, Rosalind J. Neuman5, John I. Nurnberger6, John P. Rice5, Jay A. Tischfield9, Laura J. Bierut5
1Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, USA
2University of Minnesota, Minneapolis, USA
3Virginia Commonwealth University, Richmond, USA
4Ankara University, Ankara, Turkey
5Washington University in St. Louis, St. Louis, USA
6Indiana University Bloomington, USA
7University of Connecticut, Farmington, USA
8University of Iowa, Iowa City, USA
9Rutgers University, Piscataway, USA

Tóm tắt

Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that (1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and (2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.

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