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

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Abstract

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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Acknowledgments

Financial Disclosures Drs. LJ Bierut, AM Goate, JR Rice, and S Saccone are listed as inventors on the patent “Markers for Addiction” (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Dr. Bierut has acted as a consultant for Pfizer, Inc. in 2008. All other authors report no competing interests. Study of Addiction: Genetics and Environment (SAGE). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the GWAS funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease”(HHSN268200782096C). Dr. A Agrawal receives support from NIH DA23668. Dr. LJ Bierut receives support from NIH DA21237. Dr. J Derringer receives support from NIH DA029377 and GM081739. Dr. RA Grucza receives support from NIH AA017444 and DA026612. Dr. S Saccone receives support from NIH DA024722.

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Authors and Affiliations

  1. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, 80309-0447, USA

    Jaime Derringer

  2. University of Minnesota, Minneapolis, USA

    Robert F. Krueger

  3. Virginia Commonwealth University, Richmond, USA

    Danielle M. Dick & Fazil Aliev

  4. Ankara University, Ankara, Turkey

    Fazil Aliev

  5. Washington University in St. Louis, St. Louis, USA

    Richard A. Grucza, Scott Saccone, Arpana Agrawal, Alison M. Goate, Peng Lin, Rosalind J. Neuman, John P. Rice & Laura J. Bierut

  6. Indiana University, Bloomington, USA

    Howard J. Edenberg & John I. Nurnberger Jr.

  7. University of Connecticut, Farmington, USA

    Victor M. Hesselbrock

  8. University of Iowa, Iowa City, USA

    John R. Kramer

  9. Rutgers University, Piscataway, USA

    Jay A. Tischfield

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  1. Jaime Derringer
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Correspondence to Jaime Derringer.

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Derringer, J., Krueger, R.F., Dick, D.M. et al. The Aggregate Effect of Dopamine Genes on Dependence Symptoms Among Cocaine Users: Cross-Validation of a Candidate System Scoring Approach. Behav Genet 42, 626–635 (2012). https://doi.org/10.1007/s10519-012-9531-4

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