Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0424, USA.
Mol Psychiatry. 2011 Nov;16(11):1117-29. doi: 10.1038/mp.2010.96. Epub 2010 Sep 14.
We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
我们使用临床抗精神病药物疗效试验 (CATIE) 和精神分裂症全基因组关联研究的分子遗传学数据 (MGS-GAIN) 支持的遗传关联信息网络 (MGS-GAIN) 精神分裂症数据集进行了数据挖掘分析，并对两个数据集 P 值均≤0.05 的所有标记物进行了生物信息优先级排序。在这个过程中，我们发现 CMYA5 基因中有两个非同义标记物 rs3828611 和 rs10043986，在 CATIE 和 MGS-GAIN 样本中均表现出名义显著性。在对 CATIE 和 MGS-GAIN 样本的联合分析中，rs4704591 被确定为基因中最显著的标记物。连锁不平衡分析表明，这些标记物处于低 LD（3828611-rs10043986，r(2)=0.008；rs10043986-rs4704591，r(2)=0.204）。此外，CMYA5 据报道与 DTNBP1 基因物理相互作用，DTNBP1 是精神分裂症的一个有前途的候选基因，这表明 CMYA5 可能参与了相同的生物学途径和过程。基于这些信息，我们对这三个单核苷酸多态性进行了复制研究。在我们的爱尔兰样本中，rs3828611 结果存在矛盾，没有进一步研究就被排除了。另外两个标记物在 23 个其他独立数据集得到了验证。在对所有 23 个复制样本（家系样本，912 个家系 4160 个个体；病例对照样本，11380 个病例和 15021 个对照）的荟萃分析中，我们发现这两个标记物与精神分裂症显著相关（rs10043986，比值比（OR）=1.11，95%置信区间（CI）=1.04-1.18，P=8.2×10(-4)；rs4704591，OR=1.07，95%CI=1.03-1.11，P=3.0×10(-4)）。对于 22 个高加索复制样本，结果也很显著（rs10043986，OR=1.11，95%CI=1.03-1.17，P=0.0026；rs4704591，OR=1.07，95%CI=1.02-1.11，P=0.0015）。此外，条件单倍型分析表明，在这两个标记物中观察到的关联信号是独立的。基于这些结果，我们得出结论，CMYA5 与精神分裂症相关，需要进一步研究该基因。
