Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia
Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia
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DOI：
10.1038/ejhg.2008.247
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发表时间：
2009-06-01
影响因子：
5.2
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Hattori, Eiji;Nakajima, Mizuho;Yoshikawa, Takeo
多巴胺D4受体基因第3外显子的可变数目串联重复序列（VNTR）多态性与多种精神疾病/特征之间存在关联。我们研究了不同长度的VNTR等位基因在日本人群中的分布，发现如前所述，等位基因“7 R”的大小在日本人群中比在高加索人群中（类似于20%）要罕见得多（0.5%）。这对先前提出的假设提出了挑战，即有利于等位基因7 R的正选择有助于其高频率。为了进一步解决选择的问题，我们进行了测序的VNTR区域不仅从人类，而且从黑猩猩样品，并作出推断的祖先重复基序和单倍型通过使用系统发育分析程序。最常见的4 R变体被认为是早期提出的祖先单倍型。然而，在一个基因树的VNTR构建的基础上，这个推断的祖先单倍型，等位基因7 R有五个后代单倍型在相对较长的血统，遗传漂变可能有重大影响。我们还测试了这种长度多态性与精神分裂症的相关性，研究了两个日本样本集（一个有570例病例和570例对照，另一个有124个家系）。在两个数据集中均未发现等位基因7 R与精神分裂症相关的证据。总的来说，这项研究表明，VNTR的变化没有足够大的影响，导致选择或检测到的关联与精神分裂症的研究中的样本量适中。European Journal of Human Genetics（2009）17，793-801; doi：10.1038/ejhg.2008.247; 2008年12月17日在线发表
Associations have been reported between the variable number of tandem repeat (VNTR) polymorphisms in the exon 3 of dopamine D4 receptor gene gene and multiple psychiatric illnesses/traits. We examined the distribution of VNTR alleles of different length in a Japanese cohort and found that, as reported earlier, the size of allele '7R' was much rarer (0.5%) in Japanese than in Caucasian populations (similar to 20%). This presents a challenge to an earlier proposed hypothesis that positive selection favoring the allele 7R has contributed to its high frequency. To further address the issue of selection, we carried out sequencing of the VNTR region not only from human but also from chimpanzee samples, and made inference on the ancestral repeat motif and haplotype by use of a phylogenetic analysis program. The most common 4R variant was considered to be the ancestral haplotype as earlier proposed. However, in a gene tree of VNTR constructed on the basis of this inferred ancestral haplotype, the allele 7R had five descendent haplotypes in relatively long lineage, where genetic drift can have major influence. We also tested this length polymorphism for association with schizophrenia, studying two Japanese sample sets (one with 570 cases and 570 controls, and the other with 124 pedigrees). No evidence of association between the allele 7R and schizophrenia was found in any of the two data sets. Collectively, this study suggests that the VNTR variation does not have an effect large enough to cause either selection or a detectable association with schizophrenia in a study of samples of moderate size. European Journal of Human Genetics (2009) 17, 793-801; doi: 10.1038/ejhg.2008.247; published online 17 December 2008