A genome-wide association study implicates diacylglycerol kinase η (DGKH) and several other genes in the etiology of bipolar disorder
A genome-wide association study implicates diacylglycerol kinase η (DGKH) and several other genes in the etiology of bipolar disorder
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DOI：
10.1038/sj.mp.4002012
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发表时间：
2008-02-01
影响因子：
11
通讯作者：
McMahon, F. J.
中科院分区：
文献类型：
--
作者：
Baum, A. E.;Akula, N.;McMahon, F. J.
长期以来，双相情感障碍的遗传基础一直被认为是复杂的，可能涉及多个基因，但分析这种复杂性的人群的方法直到最近才出现。我们对来自欧洲的两个独立病例对照样本中超过 550 000 个单核苷酸多态性 (SNP) 进行了基因分型，开展了双相情感障碍的全基因组关联研究。使用汇集的 DNA 进行初始关联筛选，并通过个体基因分型确认选定的 SNP。虽然 DNA 池降低了检测遗传关联的能力，但可以节省大量成本并提高效率。总共 88 个 SNP，代表 80 个不同的基因，在两个样本中都满足先前的复制标准。效应大小适中：没有检测到具有大效应的单个 SNP。在选择用于个体基因分型的 37 个 SNP 中，在二酰甘油激酶 eta 第一个内含子内的标记处检测到最强的关联信号（DGKH；P = 1.5 x 10(-8)，实验范围内 P < 0.01，OR = 1.59）。该基因编码 DGKH，这是锂敏感磷脂酰肌醇途径中的关键蛋白。这项双相情感障碍的第一个全基因组关联研究表明，几个基因（每个基因的影响不大）可重复地影响疾病风险。双相情感障碍可能是一种多基因疾病。
The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P = 1.5 x 10(-8), experiment-wide P < 0.01, OR = 1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.