Genetic factors contribute to the development of alcohol dependence (AD). The only specific genes known to affect risk for AD are some of those coding enzymes important for ethanol metabolism. Promising linkage regions have been identified in two genome scans, but for genetically heterogeneous disorders like AD, strategies that rely purely on linkage for gene localization are not likely to result in gene identification. Linkage disequilibrium (LD) studies, using methods such as the transmission-disequilibrium test (TDT) of Spielman et al. (1993), provide a possible solution; these methods have the power to identify much shorter genomic regions likely to contain susceptibility loci than linkage methods, without being subject to population stratification error. Additionally, newly developed methods can greatly decrease risk of stratification error in case-control studies. LD studies (TDT and case-control) therefore are complementary to conventional linkage approaches. Specialized clinical materials must be collected, with rigorous ascertainment. We started a project collecting family trios with an alcohol-dependent proband in December 1996, and have now collected >150 predominantly European-American small nuclear families. We now propose to collect a sample of 360 additional small nuclear families, predominantly African-American, suitable for TDT analyses of AD, and a case-control sample of 1000 African-American (AA) subjects (500 ill and 500 well). The AA population, because it is recently admixed, is particularly advantageous for LD mapping, and LD has been demonstrated at great distances in AA populations. Families and unrelated subjects will be collected at Yale, Univ. CT, and MUSC, using the SSAGA as the primary diagnostic instrument. Additional phenotypic data will be collected using the FHAM and the NEO PI-R (personality). We will use both quantitative and categorical TDT analyses and make case-control comparisons with correction for admixture. Molecular studies will focus on genomic regions previously identified through linkage genome scans as being likely to contain susceptibility loci, plus positional candidate gene linkage disequilibrium and haplotype studies as the clinical sample is developed, with the goal of eventually using this sample for a whole-genome LD scan in a future study. New polymorphisms will be identified in candidate regions. Collection of a sample such as the one proposed here is a necessary step towards identifying specific genes that predispose for AD. Loci identified will be expected to have particular relevance for the AA community.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Ren, Zhaoxia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Smith, Andrew H; Ovesen, Peter L; Skeldal, Sune et al. (2018) Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcohol Clin Exp Res 42:2337-2348
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus. Mol Psychiatry 23:154-160
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers. Acta Psychiatr Scand 137:148-156
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Polimanti, Renato; Gelernter, Joel (2018) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet 177:113-125
Zhou, Hang; Cheng, Zhongshan; Bass, Nicholas et al. (2018) Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. Transl Psychiatry 8:208
Montalvo-Ortiz, Janitza L; Zhou, Hang; D'Andrea, Ivana et al. (2018) Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response. Mol Psychiatry 23:2277-2286
Cheng, Zhongshan; Zhou, Hang; Sherva, Richard et al. (2018) Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biol Psychiatry 84:762-770
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9
Cabana-Domínguez, Judit; Arenas, Concepció; Cormand, Bru et al. (2018) MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence. Transl Psychiatry 8:173

Showing the most recent 10 out of 192 publications