Human Molecular Genetics Advance Access originally published online on November 3, 2006
Human Molecular Genetics 2006 15(24):3498-3507; doi:10.1093/hmg/ddl426
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Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations
1 Division of Human Genetics, Department of Psychiatry, 2 Department of Neurobiology, 3 Department of Genetics and 4 VA CT Healthcare Center, Yale University School of Medicine, VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA, 5 Department of Medicine (Genetics Program), 6 Department of Biostatistics, 7 Department of Neurology, 8 Department of Genetics & Genomics, and 9 Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA, 10 Alcohol and Drug Abuse Treatment Program, McLean Hospital, Belmont, MA, USA, 11 Department of Psychiatry, Harvard Medical School, Boston, MA, USA, 12 Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA and 13 Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
* To whom correspondence should be addressed. Tel: +1 2039325711, ext 3590; Fax: , +1 2039374741; Email: joel.gelernter{at}yale.edu
Received August 24, 2006; Accepted October 26, 2006
Nicotine dependence (ND) is a moderately heritable trait. We ascertained a set of 1615 subjects in 632 families [319 African-American (AA) and 313 European-American (EA)] based on affected sibling pairs with cocaine or opioid dependence. Subjects were interviewed with the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Previously, we identified a modest linkage peak (LOD score =1.97) for ND in the EA part of the sample on chromosome 11q23, a region that includes the NCAM1–TTC12–ANKK1–DRD2 gene cluster. DRD2 and NCAM1 are functional candidate genes for substance dependence; the TTC12 and ANKK1 loci are not well characterized. We genotyped a set of 43 single nucleotide polymorphisms (SNPs) spanning this region, and performed family-based association and haplotype analysis. There was relatively weak evidence for association of the flanking DRD2 and NCAM1 markers to ND, but very strong evidence of association of multiple SNPs at TTC12 and ANKK1 in both populations (minimal P=0.0007 in AAs and minimal P=0.00009 in EAs), and in the pooled sample, as well as strong evidence for highly significant association of a single haplotype spanning TTC12 and ANKK1 to ND in the pooled sample (P=0.0000001). We conclude that a risk locus for ND, important both in AAs and EAs, maps to a region that spans TTC12 and ANKK1. Functional studies of these loci are warranted. These results provide additional information useful in evaluating the many earlier discrepant findings regarding association of DRD2 with substance dependence.
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