Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2011;6(8):e23812. doi: 10.1371/journal.pone.0023812. Epub 2011 Aug 29.
Any given single nucleotide polymorphism (SNP) in a genome may have little or no functional impact. A biologically significant effect may possibly emerge only when a number of key SNP-related genotypes occur together in a single organism. Thus, in analysis of many SNPs in association studies of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC bipolar dataset were use for replication, 469 of the 803 SNP were present in the WTCCC dataset either directly (n = 132) or by imputation (n = 337) covering 51 of our selected genes. We found three clusters of patient-specific 3×SNP combinations in the WTCCC dataset. Different SNPs were involved in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder.
在基因组中，任何给定的单核苷酸多态性 (SNP) 可能几乎没有或没有功能影响。只有当一个生物体中同时出现许多关键的 SNP 相关基因型时，才可能出现生物学上的显著影响。因此，在分析复杂疾病关联研究中的许多 SNP 时，研究基因型的组合可能会很有用。在双相情感障碍的背景下，与信号转导相关的基因，例如离子通道基因，可能在这方面具有重要意义。在本研究中，我们分析了与信号转导方面相关的 55 个基因中的 803 个 SNP，并计算了 1355 名对照和 607 名双相情感障碍患者的 3×803 SNP 基因型的所有三种基因型组合。确定了四个与患者特异性相关的组合簇。置换检验表明，其中一些组合可能与双相情感障碍有关。使用 WTCCC 双相数据集进行复制，803 个 SNP 中有 469 个直接存在于 WTCCC 数据集（n=132）或通过推断存在于 WTCCC 数据集（n=337），涵盖了我们选择的 51 个基因。我们在 WTCCC 数据集发现了三个与患者特异性相关的 3×SNP 组合簇。在两个数据集的簇中涉及不同的 SNP。本研究对 SNP 基因型组合的分析支持双相情感障碍遗传结构中遗传异质性和相互作用的作用。
