Human Molecular Genetics Advance Access published online on May 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi177
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1 Program in Genomics and Bioinformatics on Drug Addiction, Department of Psychiatry, University of Texas Health Science Center at San Antonio
* To whom correspondence should be addressed. 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 8 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 2,037 smokers and non-smokers from 602 nuclear families of African-or European-American (AA or EA) 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-rs1452371-rs2060762 in the AA sample that 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-rs1452371-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.
Received April 1, 2005
Revised April 21, 2005
Accepted April 29, 2005
Article
Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence
2 The ACT Tobacco Center, University of Mississippi Schools of Dentistry and Medicine;
3 Department of Criminology and Criminal Justice, University of Memphis;
4 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH.
Ming D. Li, E-mail: lim2{at}uthscsa.edu
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