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Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene

Molecular Psychiatry volume 19, pages 717–723 (2014)Cite this article

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Abstract

We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8 90 000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B (‘family with sequence similarity 53, member B’) locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 × 10−8. The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 × 10−9 in the EA discovery sample. SNP rs2456778, which maps to CDK1 (‘cyclin-dependent kinase 1’), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 × 10−8). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies.

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Acknowledgements

We appreciate the work in recruitment and assessment provided at McLean Hospital by Roger Weiss at the Medical University of South Carolina by Kathleen Brady and Raymond Anton and at the University of Pennsylvania by David Oslin. Genotyping services for a part of our GWAS study were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). We are grateful to Ann Marie Lacobelle, Michelle Cucinelli, Christa Robinson and Greg Dalton-Kay for their excellent technical assistance, to the SSADDA interviewers, led by Yari Nuñez and Michelle Slivinsky, who devoted substantial time and effort to phenotype the study sample and to John Farrell for database management assistance. This study was supported by National Institutes of Health Grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535 and the VA Connecticut and Philadelphia VA MIRECCs. The publicly available data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. 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 genome-wide association studies 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 data sets 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).

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Authors and Affiliations

  1. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    J Gelernter

  2. Department of Psychiatry, VA CT Healthcare Center, West Haven, CT, USA

    J Gelernter

  3. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    J Gelernter & H Zhao

  4. Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA

    J Gelernter

  5. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    R Sherva, R Koesterer & L Farrer

  6. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    L Almasy

  7. Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA

    H Zhao

  8. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    H R Kranzler

  9. Department of Psychiatry, Philadelphia VA Medical Center, Philadelphia, PA, USA

    H R Kranzler

  10. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    L Farrer

  11. Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

    L Farrer

  12. Department of Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA

    L Farrer

  13. Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA, USA

    L Farrer

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  1. J Gelernter
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Correspondence to J Gelernter.

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Competing interests

Although unrelated to the current study, Dr Kranzler has been a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer and Roche. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, Abbott and Pfizer.

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Gelernter, J., Sherva, R., Koesterer, R. et al. Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry 19, 717–723 (2014). https://doi.org/10.1038/mp.2013.99

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