Abstract
Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD–MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD–MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD–MDE in AAs (lod=3.8, genomewide empirical p=0.016; point-wise p=0.00001). A nearly genomewide significant linkage was identified for CD–MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod)=2.95, genomewide empirical p=0.055; point-wise p=0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod=3.28, genomewide empirical p=0.046; point-wise p=0.00053). This is the first GWLS for CD–MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5A1, UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here.
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Acknowledgements
We are grateful to the volunteer families and individuals who participated in this research study. Genotyping services were provided by the Center for Inherited Disease Research (CIDR) and Yale (Keck Center). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). Genotyping was supported in part by a Yale CTSA and NIH Neuroscience Microarray Consortium award U24 NS051869-02S1. We thank Dr Joan Kaufman at for reading the paper and giving insightful comments. We are grateful to Ann Marie Lacobelle and Greg Kay for their excellent technical assistance. This study was supported by National Institute on Drug Abuse (NIDA) Grants K01 DA24758, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, and the VA Connecticut REAP center, a VA MERIT grant, and the VA Connecticut MIRECC Center.
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Drs Yang, Han, and Gelernter report no financial relationships with commercial interests. Dr Gelernter reports that he has received compensation for professional services in the previous 3 years from the following entities: Yale University School of Medicine, Veterans Affairs Healthcare System (VA), and the National Institutes of Health (NIAAA, NIDA, and NIMH) and related to academic lectures and editorial functions in various scientific venues (including the ACNP). Dr Kranzler reports consulting arrangements with Alkermes, GlaxoSmithKline, and Gilead Sciences, and has received research support from Merck and Company, Bristol-Myers Squibb Company. He also reports associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson and Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and Dr Kranzler receives support from ACTIVE. Dr Farrer received a research grant from Eisai Pharmaceuticals and consultant fees from Novartis Pharmaceuticals.
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Yang, BZ., Han, S., Kranzler, H. et al. A Genomewide Linkage Scan of Cocaine Dependence and Major Depressive Episode in Two Populations. Neuropsychopharmacol 36, 2422–2430 (2011). https://doi.org/10.1038/npp.2011.122
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DOI: https://doi.org/10.1038/npp.2011.122
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