Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder
Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder
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DOI：
10.1016/j.ajhg.2011.01.017
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发表时间：
2011-03-11
影响因子：
9.8
通讯作者：
Noethen, Markus M.
中科院分区：
文献类型：
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作者：
Cichon, Sven;Muehleisen, Thomas W.;Noethen, Markus M.
我们对双相情感障碍（BD）——一种常见的神经精神疾病进行了全基因组关联研究（GWAS）以及一项后续研究。在GWAS中，我们对682名双相情感障碍患者和1300名对照者的499,494个常染色体单核苷酸多态性（SNP）以及12,484个X染色体SNP进行了研究。在第一步后续研究中，我们对1729名双相情感障碍患者和2313名对照者检测了最显著的48个SNP。8个SNP显示出与双相情感障碍名义上显著的关联，并被引入GWAS和第一步后续样本的荟萃分析中。在2411名患者和3613名对照者中，神经聚糖基因（NCAN）的遗传变异显示出与双相情感障碍全基因组显著的关联（rs1064395，p = 3.02×10⁻⁸；优势比 = 1.31）。在第二步后续研究中，我们在总计6030名患者和31,749名对照者的独立双相情感障碍样本中重复了这一发现（p = 2.74×10⁻⁴；优势比 = 1.12）。对所有研究样本的综合分析得出p值为2.14×10⁻⁹（优势比 = 1.17）。我们的研究结果提供了证据，表明rs1064395是双相情感障碍的一个常见风险因素。NCAN编码神经聚糖，一种细胞外基质糖蛋白，被认为参与细胞黏附和迁移。我们发现其在小鼠中的表达局限于皮质和海马区域。这些区域参与认知和情绪调节，并且先前通过神经心理学、神经影像学和尸检研究已表明与双相情感障碍有关。
We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 x 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 x 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 x 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.