Palmatier M A, Pakstis A J, Speed W, Paschou P, Goldman D, Odunsi A, Okonofua F, Kajuna S, Karoma N, Kungulilo S, Grigorenko E, Zhukova O V, Bonne-Tamir B, Lu R-B, Parnas J, Kidd J R, DeMille M M C, Kidd K K
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Mol Psychiatry. 2004 Sep;9(9):859-70. doi: 10.1038/sj.mp.4001496.
A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3' rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia.
最近一项研究在大量阿什肯纳兹犹太人样本中发现，精神分裂症与儿茶酚 - O - 甲基转移酶（COMT）基因中三个多态性位点的特定单倍型之间存在高度显著的关联：一个内含子1单核苷酸多态性（dbSNP rs737865）、外显子4功能性单核苷酸多态性（Val158Met，dbSNP rs165688）以及一个下游单核苷酸多态性（dbSNP rs165599）。随后发现，该单倍型与源自正常大脑皮质组织的COMT cDNA水平较低有关，这很可能是由于顺式作用元件所致。作为评估此单倍型在阿什肯纳兹犹太人以外人群中是否与精神分裂症相关的第一步，我们在代表世界所有主要地区的38个群体中研究了该单倍型。在我们之前关于COMT基因四个多态性位点（包括Val158Met多态性）数据的基础上，我们对内含子1的rs737865和3'端的rs615599位点进行了分型，还纳入了一个新的内含子1插入缺失多态性，得出了38个全球分布群体中正常个体的七位点单倍型频率，其中包括一个阿什肯纳兹犹太人样本。我们报告称，与精神分裂症相关的单倍型在全球人群中存在显著的异质性。尽管精神分裂症在世界各地的发病率大致相同，但这三个位点的、与精神分裂症相关的单倍型频率在南美洲为0%，在西南亚为37.1%。假设已发表的外显子4 Val158Met单核苷酸多态性与精神分裂症之间的关联是由于连锁不平衡，这些新的单倍型数据支持这样一种假说，即存在一个与rs737865位点连锁的相关顺式变异，可能就在驱动大脑中主要形式的COMT转录的P2启动子上游。先前描述的位于P2启动子内的HindIII限制性位点多态性在所有群体中都有所不同，可能会在未来的精神分裂症研究中提供重要信息。
