Yu Yi, Panhuysen Carolien, Kranzler Henry R, Hesselbrock Victor, Rounsaville Bruce, Weiss Roger, Brady Kathleen, Farrer Lindsay A, Gelernter Joel
Department of Medicine, Genetics Program, Boston University School of Medicine, MA, USA.
Hum Mol Genet. 2006 Jul 15;15(14):2192-9. doi: 10.1093/hmg/ddl144. Epub 2006 Jun 1.
We report here a study considering association of alleles and haplotypes at the DOPA decarboxylase (DDC) locus with the DSM-IV diagnosis of nicotine dependence (ND) or a quantitative measure for ND using the Fagerstrom Test for Nicotine Dependence (FTND). We genotyped 18 single nucleotide polymorphisms (SNPs) spanning a region of approximately 210 kb that includes DDC and the genes immediately flanking DDC in 1,590 individuals from 621 families of African-American (AA) or European-American (EA) ancestry. Evidence of association (family-based tests) was observed with several SNPs for both traits (0.0002<or=P<or=0.04). The most significant result was obtained for the relationship of FTND score to SNP rs12718541 (AA families: P=0.002; EA families: P=0.03; all families: P=0.0002) which is in the same intron as the splice site for a neuronal isoform of human DDC lacking exons 10-15. Haplotype analysis did not reveal any SNP combination with stronger evidence for association than rs12718541 alone. Although sequence analysis suggests that rs12718541 may be an intronic splicing enhancer, further studies are needed to determine whether a direct link exists between an alternatively spliced form of DDC and predisposition to ND. These findings confirm a previous report of association of DDC with ND, localize the causative variants to the 3' end of the coding region and extend the association to multiple population groups.
我们在此报告一项研究，该研究探讨了多巴脱羧酶（DDC）基因座上的等位基因和单倍型与尼古丁依赖（ND）的DSM-IV诊断或使用尼古丁依赖Fagerstrom测试（FTND）对ND进行定量测量之间的关联。我们对18个单核苷酸多态性（SNP）进行了基因分型，这些SNP跨越了约210 kb的区域，该区域包括DDC以及来自621个非裔美国人（AA）或欧裔美国人（EA）血统家庭的1590名个体中紧邻DDC的基因。观察到几个SNP与这两个性状均存在关联证据（基于家系的测试）（0.0002≤P≤0.04）。对于FTND评分与SNP rs12718541的关系，获得了最显著的结果（AA家庭：P = 0.002；EA家庭：P = 0.03；所有家庭：P = 0.0002），该SNP与人类DDC神经元异构体缺乏外显子10-15的剪接位点位于同一内含子中。单倍型分析未发现任何比单独的rs12718541具有更强关联证据的SNP组合。尽管序列分析表明rs12718541可能是一个内含子剪接增强子，但仍需要进一步研究以确定DDC的可变剪接形式与ND易感性之间是否存在直接联系。这些发现证实了先前关于DDC与ND关联的报告，将致病变异定位到编码区域的3'端，并将该关联扩展到多个群体。
