Human Molecular Genetics Advance Access originally published online on May 6, 2005
Human Molecular Genetics 2005 14(12):1691-1698; doi:10.1093/hmg/ddi177
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence
Jennie Z. Ma1,
Joke Beuten1,
Thomas J. Payne2,
Randolph T. Dupont3,
Robert C. Elston4 and
Ming D. Li1,*
1Program in Genomics and Bioinformatics on Drug Addiction, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA,
2The ACT Tobacco Center, University of Mississippi Schools of Dentistry and Medicine, Jackson, MS, USA,
3Department of Criminology and Criminal Justice, University of Memphis, Memphis, TN, USA and
4Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed at: MSC 7792, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel: +1 2105670830; Fax: +1 2105670853; Email: lim2{at}uthscsa.edu
Received April 1, 2005; Revised April 21, 2005; Accepted April 29, 2005
DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a ‘suggestive linkage’ to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerström test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01–0.04). Haplotype-based association analysis revealed a protective T–G–T–G haplotype for rs921451–rs3735273–rs1451371–rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=–2.78, P=0.006 for HSI). In contrast, we found a high-risk T–G–T–G haplotype for a different SNP combination in the EA sample, rs921451–rs3735273–rs1451371–rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.
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