Costas Javier, Carrera Noa, Domínguez Eduardo, Vilella Elisabet, Martorell Lourdes, Valero Joaquín, Gutiérrez-Zotes Alfonso, Labad Antonio, Carracedo Angel
Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, University of Santiago Hospital Complex, Santiago de Compostela, Spain.
Hum Genet. 2009 Jan;124(6):607-13. doi: 10.1007/s00439-008-0584-7. Epub 2008 Nov 6.
The number and frequency of susceptibility alleles at loci associated to most psychiatric disorders is largely unknown, in spite of its relevance for the design of studies aiming to find these alleles. Both, common polymorphisms and rare mutations may contribute to the genetic susceptibility to complex psychiatric disorders, being the relative relevance of each type of variation currently under debate. Here, we confirmed the existence of a common protective haplotype against schizophrenia at the dopamine D(3) receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel-Haenszel chi(2) P value = 0.00227; OR = 0.79, 95% CI 0.68-0.92, based on 794 cases and 1,078 controls from three independent populations of European origin). This protective haplotype is at very low frequency in Sub-Saharan Africans (median 0.06) and at intermediate frequencies in other populations (median 0.25). We also revealed, by examining the patterns of linkage disequilibrium around this gene, that the protective haplotype has reached high frequency in non-African populations due to selection acting, most probably, on a linked functional polymorphism, the non-synonymous single nucleotide polymorphism Ser9Gly (rs6280), also at DRD3. Thus, this finding shows that the natural selection may play a role in the existence of common alleles conferring different susceptibility to schizophrenia.
尽管与大多数精神疾病相关的基因座上易感等位基因的数量和频率对于旨在寻找这些等位基因的研究设计具有重要意义，但目前仍知之甚少。常见的多态性和罕见突变都可能导致对复杂精神疾病的遗传易感性，目前每种变异类型的相对相关性仍在争论中。在这里，我们通过复制并汇总分析先前的数据，证实了多巴胺D(3)受体（DRD3）基因存在一种针对精神分裂症的常见保护性单倍型（基于来自三个欧洲裔独立人群的794例病例和1,078例对照，Mantel-Haenszel卡方检验P值 = 0.00227；OR = 0.79，95%置信区间0.68 - 0.92）。这种保护性单倍型在撒哈拉以南非洲人的频率非常低（中位数为0.06），在其他人群中的频率处于中等水平（中位数为0.25）。我们还通过研究该基因周围的连锁不平衡模式发现，由于自然选择作用于一个与之连锁的功能性多态性，即DRD3基因上的非同义单核苷酸多态性Ser9Gly（rs6280），这种保护性单倍型在非非洲人群中达到了高频。因此，这一发现表明自然选择可能在赋予精神分裂症不同易感性的常见等位基因的存在中发挥作用。
