Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder
Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder
复制标题
DOI：
10.1002/ajmg.b.30303
复制
发表时间：
2006-06-05
影响因子：
2.8
通讯作者：
Mueller-Myhsok, Bertram
中科院分区：
文献类型：
--
作者：
Barden, Nicholas;Harvey, Mario;Mueller-Myhsok, Bertram
我们以前的遗传分析的结果，从法裔加拿大人口的家系表明，区间划定的标记12号染色体上，D12 S86和D12 S378，是最有可能的基因组区域包含情感障碍的易感基因。使用来自同一人群的病例/对照样本（n = 427）进行的微卫星标记关联研究显示，双极表型和标记NBG 6之间存在显著的等位基因关联。由于该标记位于P2 RX 7基因的内含子9中，我们分析了周围基因组区域在调控、编码和内含子/外显子连接序列中多态性的存在。在病例/对照样品中对二十四（24）个SNP进行基因分型，并且在所有谱系中的12个SNP用于连锁分析。等位基因，基因型或基于家庭的关联研究表明存在两个易感基因座，P2 RX 7和CaMKK 2基因。在双相情感障碍家族中，在非同义SNP P2 RX 7-E13 A（rs 2230912，P值= 0.000708）处观察到最强的关联，这是由于突变G等位基因过度传递给受影响的后代。这种Gln 460 Arg多态性发生在人类和啮齿动物之间保守的氨基酸处，并且位于P2 X7受体的C-末端结构域，已知对于正常P2 RX 7功能是必需的。(c)2006 Wiley-Liss，Inc.
Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers on chromosome 12, D12S86 and D12S378, was the most probable genomic region to contain a susceptibility gene for affective disorders. Association studies with microsatellite markers using a case/control sample from the same population (n = 427) revealed significant allelic associations between the bipolar phenotype and marker NBG6. Since this marker is located in intron 9 of the P2RX7 gene, we analyzed the surrounding genomic region for the presence of polymorphisms in regulatory, coding and intron/exon junction sequences. Twenty four (24) SNPs were genotyped in a case/control sample and 12 SNPs in all pedigrees used for linkage analysis. Allelic, genotypic or family-based association studies suggest the presence of two susceptibility loci, the P2RX7 and CaMKK2 genes. The strongest association was observed in bipolar families at the non-synonymous SNP P2RX7-E13A (rs2230912, P-value = 0.000708), which results from an over-transmission of the mutant G-allele to affected offspring. This Gln460Arg polymorphism occurs at an amino acid that is conserved between humans and rodents and is located in the C-terminal domain of the P2X7 receptor, known to be essential for normal P2RX7 function. (c) 2006 Wiley-Liss, Inc.