INSERM U894 (exU675), Center of Psychiatry and Neurosciences, Paris, France.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Apr 16;34(3):492-9. doi: 10.1016/j.pnpbp.2010.02.003. Epub 2010 Feb 6.
The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.
We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.
Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p=0.01, Odds Ratio=1.5, 95% Confidence Interval=1.1-2.2), and the intergenic rs2242592 (p=2.10(-4), OR=1.8, 95%CI=1.3-2.5). A significant SNP-SNP interaction was also found (p<10(-5), OR=2.0, 95%CI=1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.
Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.
编码多巴胺 D2 受体（DRD2）的基因被认为是精神分裂症最相关的候选基因之一。然而，遗传研究的结果相互矛盾，而有前途的 TaqIA 变体/rs1800497 已被映射到一个新的基因ANKK1 中。
我们使用病例对照关联研究比较了 144 名独立患者和 142 名匹配的健康对照，以及 108 个三核苷酸对 DRD2 和 ANKK1 基因进行了十一个单核苷酸多态性（SNP）的研究，进行了基因传递不平衡测试。这项经典的遗传研究结合了人类变异的系统发生树基关联测试，以及ANKK1 的种间进化研究。
病例对照研究，随后进行 108 个三核苷酸对的基于家庭的关联分析进行复制，显示 ANKK1 rs1800497（p=0.01，优势比=1.5，95%置信区间=1.1-2.2）与精神分裂症之间存在关联，并且与基因间 rs2242592（p=2.10(-4)，OR=1.8，95%CI=1.3-2.5）存在关联。还发现了显著的 SNP-SNP 相互作用（p<10(-5)，OR=2.0，95%CI=1.6-2.5）。基于系统发育的关联测试也确定了这两种多态性与精神分裂症之间的关联。最后，对黑猩猩、猩猩、恒河猴和人类物种的序列进行种间比较表明，ANKK1 特异性参与了人类谱系。
基因间 rs2242592 似乎参与了精神分裂症的遗传易感性，而 ANKK1 rs1800497 似乎具有修饰作用而不是因果作用。最后，ANKK1 可能是一种特定的人类谱系特征，参与了一种特定的人类疾病，即精神分裂症。
