RAPID COMMUNICATIONADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studiesLuo, Xingguanga b; Kranzler, Henry R.c; Zuo, Lingjuna b; Yang, Bao-zhua b; Lappalainen, Jaakkoa b; Gelernter, Joela bAuthor Information aDepartment of Psychiatry, Yale University School of Medicine, New Haven, Connecticut bVA Connecticut Healthcare System, West Haven Campus, Connecticut cAlcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut, USA Sponsorship: This work was supported in part by funds from the US Department of Veterans Affairs (the VA Medical Research Program, and the VA Connecticut–Massachusetts Mental Illness Research, Education and Clinical Center (MIRECC), and the VA Research Enhancement Award Program (REAP) research center), National Institute of Mental Health (NIMH) grant K02-MH01387, National Institute on Drug Abuse (NIDA) grants R01-DA12849, R01-DA12690, and K24-DA15105, National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants R01-AA11330, P50-AA12870, K08-AA13732 and K24-AA13736, National Center for Research Resources (NCRR) grant M01-RR06192 (University of Connecticut General Clinical Research Center), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (X. Luo) and the NIH Biological Sciences Training Program (BSTP) MH14276 (B.Z. Yang). Correspondence and requests for reprints to Joel Gelernter, Yale University School of Medicine, VA Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA Tel: +1 203 9325711; fax: +1 203 9373897; e-mail: [email protected] Received 13 May 2005 Accepted 4 August 2005 Pharmacogenetics and Genomics: November 2005 - Volume 15 - Issue 11 - p 755-768 doi: 10.1097/01.fpc.0000180141.77036.dc Buy Metrics Abstract We found strong associations between ADH4 gene variation and alcohol and drug dependence by the Hardy–Weinberg Disequilibrium (HWD) test and case–control association analysis in an initial study. The present study aimed to confirm these findings by controlling for population stratification and admixture effects to which the HWD test and case–control association methods may be vulnerable. In addition to 365 unrelated healthy controls and 560 unrelated cases in the initial study, we evaluated 104 small nuclear families with affected offspring who had diagnoses of alcohol and/or drug dependence. Seven single nucleotide polymorphisms (SNPs) at the ADH4 gene locus were genotyped in all subjects, and 38 unlinked ancestry-informative markers were also genotyped in unrelated cases and controls. Structured association analysis demonstrated that the genotypes of six ADH4 markers were associated with alcohol dependence, and all seven ADH4 markers were associated with drug dependence (P=10−6–0.047). Logistic regression analysis showed that: (i) the genotypes of SNP2 (rs1042363) were significantly associated with alcohol dependence and drug dependence (mainly cocaine dependence), and the genotypes of SNP3 (rs1126671) were also significantly associated with alcohol dependence and (ii) one seven-variant haplotype and one diplotype were significantly associated with alcohol dependence and other seven-variant diplotypes were significantly associated with drug dependence (including cocaine and opioid dependence). Transmission disequilibrium test, haplotype-based haplotype relative risk and genotype-based haplotype relative risk analyses all confirmed the association of the ADH4 markers with alcohol dependence and drug dependence. Using rigorous study designs that account for possible population stratification, these findings confirm and extend our original observations indicating that variation at ADH4 predisposes to alcohol and drug dependence. © 2005 Lippincott Williams & Wilkins, Inc.