Association of substance dependence phenotypes in the COGA sample

Leah Wetherill, Arpana Agrawal, Manav Kapoor, Sarah Bertelsen, Laura J. Bierut, Andrew Brooks, Danielle Dick, Michie Hesselbrock, Victor Hesselbrock, Daniel L. Koller, Nhung Le, John I. Nurnberger, Jessica E. Salvatore, Marc Schuckit, Jay A. Tischfield, Jen Chyong Wang, Xiaoling Xuei, Howard J. Edenberg, Bernice Porjesz, Kathleen BucholzAlison M. Goate, Tatiana Foroud

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Alcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2322 subjects from 118 European-American families in the Collaborative Study on the Genetics of Alcoholism sample to conduct genome-wide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the seven DSM-IV criteria for each of the four substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One single-nucleotide polymorphism (SNP), rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (P = 1.8 × 10<sup>-8</sup>), with support from surrounding imputed SNPs and replication in an independent sample [Study of Addiction: Genetics and Environment (SAGE); P = 0.02]. One SNP, rs2567261 in ARHGAP28 (Rho GTPase-activating protein 28), was associated with QUANTDEP (P = 3.8 × 10<sup>-8</sup>), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; P = 0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence. Alcohol and drug use disorders are individually heritable and share common genetic influences. 118 Caucasian COGA families were used in a GWAS of substance dependence liability, implementing a binary (h2=0.54) and quantitative (h2=0.86) phenotype, based DSM-IV criteria for dependence on alcohol, cannabis, cocaine or opioids. Genome-wide significance was detected in LOC151121 (qualitative trait), and in ARHGAP28 (quantitative trait). These results provide evidence of common variants contributing to the risk for a general liability to substance dependence.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalAddiction Biology
Volume20
Issue number3
DOIs
StatePublished - May 1 2015

Keywords

  • Alcohol dependence
  • cannabis dependence
  • cocaine dependence
  • common genetic liability
  • drug dependence
  • opioid dependence

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Pharmacology

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    Wetherill, L., Agrawal, A., Kapoor, M., Bertelsen, S., Bierut, L. J., Brooks, A., Dick, D., Hesselbrock, M., Hesselbrock, V., Koller, D. L., Le, N., Nurnberger, J. I., Salvatore, J. E., Schuckit, M., Tischfield, J. A., Wang, J. C., Xuei, X., Edenberg, H. J., Porjesz, B., ... Foroud, T. (2015). Association of substance dependence phenotypes in the COGA sample. Addiction Biology, 20(3), 617-627. https://doi.org/10.1111/adb.12153