Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.
Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.
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CACNA1C 中与精神分裂症相关的变异也会带来自闭症的风险
DOI：
10.1371/journal.pone.0133247
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Li J;Zhao L;You Y;Lu T;Jia M;Yu H;Ruan Y;Yue W;Liu J;Lu L;Zhang D;Wang L
自闭症谱系障碍 (ASD) 是一组具有很强遗传因素的神经发育障碍。许多证据表明，自闭症谱系障碍与其他精神疾病（例如精神分裂症）有共同的遗传变异。先前的研究发现钙通道与许多精神疾病的病因有关，包括精神分裂症和自闭症。检测到 CACNA1C（钙通道，电压依赖性，L 型，α1C 亚基）与精神分裂症之间存在显着关联。此外，CACNA1C 的罕见突变被认为会导致蒂莫西综合征，这是一种包括自闭症相关表型的多系统疾病。然而，没有证据表明 CACNA1C 与中国汉族人群中的自闭症之间存在关联。为了研究 CACNA1C 中的单核苷酸多态性 (SNP) 与自闭症之间的关联，我们首先在 239 名三人组中进行了 CACNA1C 中的 18 个 SNP 与自闭症之间的基于家族的关联研究。所有SNP均使用Sequenom基因分型平台进行基因分型。两个 SNP（rs1006737 和 rs4765905）有与自闭症相关的趋势。为了进一步确认这两个 SNP 与自闭症之间的关联，我们通过添加 314 个三重奏将样本量扩大到 553 个三重奏。使用基于家族的关联测试（FBAT）和 Haploview 软件进行 SNP 和单倍型的关联分析。排列测试用于单倍型分析的多重测试校正（n=10,000）。所有统计检验的显着性水平均为双尾（p<0.05）。结果表明，rs1006737 的 G 等位基因和 rs4765905 的 G 等位基因在 553 个三人组中优先传播给受影响的后代（p=0.035）。单倍型分析显示，由 rs1006737 和 rs4765905 构建的两个单倍型与自闭症显着相关（分别为 p=0.030、0.023；全局 p=0.046）。这些结果在排列校正后仍然显着（n=10,000，p=0.027）。我们的研究表明，CACNA1C 可能在中国汉族人群自闭症的遗传病因学中发挥作用。
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders (for example, schizophrenia). Previous studies detected that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit) and schizophrenia was detected. Furthermore, rare mutation in CACNA1C is suggested to cause Timothy syndrome, a multisystem disorder including autism-associated phenotype. However, there is no evidence for association between CACNA1C and autism in Chinese Han population. To investigate the association between single nucleotide polymorphisms (SNP) in CACNA1C and autism, we first performed a family-based association study between eighteen SNPs in CACNA1C and autism in 239 trios. All SNPs were genotyped by using Sequenom genotyping platform. Two SNPs (rs1006737 and rs4765905) have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. Association analyses for SNPs and haplotype were performed by using family-based association test (FBAT) and Haploview software. Permutation tests were used for multiple testing corrections of the haplotype analyses (n=10,000). The significance level for all statistical tests was two-tailed (p<0.05). The results demonstrated that G allele of rs1006737 and G allele of rs4765905 showed a preferential transmission to affected offspring in 553 trios (p=0.035). Haplotype analyses showed that two haplotypes constructed from rs1006737 and rs4765905 were significantly associated with autism (p=0.030, 0.023, respectively; Global p=0.046). These results were still significant after permutation correction (n=10,000, p=0.027). Our research suggests that CACNA1C might play a role in the genetic etiology of autism in Chinese Han population.