Autosomal linkage scan for loci predisposing to comorbid dependence on multiple substances

Authors

  • Bao-Zhu Yang,

    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. VA CT Healthcare Center, West Haven, Connecticut
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  • Shizhong Han,

    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. VA CT Healthcare Center, West Haven, Connecticut
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  • Henry R. Kranzler,

    1. Psychiatry Treatment Research Center, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Lindsay A. Farrer,

    1. Departments of Medicine, Neurology, Ophthalmology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
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  • Robert C. Elston,

    1. Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio
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  • Joel Gelernter

    Corresponding author
    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. VA CT Healthcare Center, West Haven, Connecticut
    • Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, VA CT 116A2.
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  • How to Cite this Article: Yang B-Z, Han S, Kranzler HR, Farrer LA, Elston RC, Gelernter J. 2012. Autosomal Linkage Scan for Loci Predisposing to Comorbid Dependence on Multiple Substances. Am J Med Genet Part B 159B:361–369.

  • Conflict of interest: Drs. Yang, Han, and Gelernter report no competing interests. Dr. Kranzler reports consulting arrangements with Alkermes Inc, Ortho-McNeil Pharmaceuticals, Elbion Pharmaceuticals, Solvay Pharmaceuticals, Sanofi-Aventis Pharmaceuticals, and Gilead Sciences, Inc. and has received research support from Merck and Company, Bristol-Myers Squibb Company, and Ortho-McNeil Pharmaceuticals. Dr. Farrer received a research grant from Eisai Pharmaceuticals and consultant fees from Novartis Pharmaceuticals.

Abstract

Multiple substance dependence (MSD) trait comorbidity is common, and MSD patients are often severely affected clinically. While shared genetic risks have been documented, so far there has been no published report using the linkage scan approach to survey risk loci for MSD as a phenotype. A total of 1,758 individuals in 739 families [384 African American (AA) and 355 European American (EA) families] ascertained via affected sib-pairs with cocaine or opioid or alcohol dependence were genotyped using an array-based linkage panel of single-nucleotide polymorphism markers. Fuzzy clustering analysis was conducted on individuals with alcohol, cannabis, cocaine, opioid, and nicotine dependence for AAs and EAs separately, and linkage scans were conducted for the output membership coefficients using Merlin-regression. In EAs, we observed an autosome-wide significant linkage signal on chromosome 4 (peak lod = 3.31 at 68.3 cM; empirical autosome-wide P = 0.038), and a suggestive linkage signal on chromosome 21 (peak lod = 2.37 at 19.4 cM). In AAs, four suggestive linkage peaks were observed: two peaks on chromosome 10 (lod = 2.66 at 96.7 cM and lod = 3.02 at 147.6 cM] and the other two on chromosomes 3 (lod = 2.81 at 145.5 cM) and 9 (lod = 1.93 at 146.8 cM). Three particularly promising candidate genes, GABRA4, GABRB1, and CLOCK, are located within or very close to the autosome-wide significant linkage region for EAs on chromosome 4. This is the first linkage evidence supporting existence of genetic loci influencing risk for several comorbid disorders simultaneously in two major US populations. © 2012 Wiley Periodicals, Inc.

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