Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders.
Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders.
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DOI：
10.1038/srep27491
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发表时间：
2016-06-07
影响因子：
4.6
通讯作者：
Ozaki N
中科院分区：
文献类型：
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作者：
Xing J;Kimura H;Wang C;Ishizuka K;Kushima I;Arioka Y;Yoshimi A;Nakamura Y;Shiino T;Oya-Ito T;Takasaki Y;Uno Y;Okada T;Iidaka T;Aleksic B;Mori D;Ozaki N
PSD-95 相关 PSD 蛋白在调节谷氨酸受体的密度和活性中发挥着关键作用。之前的大量研究表明，编码这些蛋白质的基因与精神分裂症 (SZ) 和自闭症谱系障碍 (ASD) 之间存在关联，这两种疾病都具有很大一部分遗传风险。我们在 Ion PGM 平台上对 562 例病例（370 名 SZ 患者和 192 名 ASD 患者）的 DLG1、DLG2、DLG4、DLGAP1、DLGAP2 和 SynGAP 的蛋白质编码区进行了测序。我们检测了 26 个罕见（次要等位基因频率 <1%）、非同义突变，并在可能的情况下进行了计算机功能分析和谱系分析。选择三个变体，DLG1 中的 G344R、DLG4 中的 G241S 和 DLGAP2 中的 R604C，在由 1315 名 SZ 患者、382 名 ASD 患者和 1793 名健康对照组成的独立样本集中进行关联分析。在病例组或对照组的任何样本中均未检测到 DLG4-G241S 和 DLGAP2-R604C，而另外一名 SZ 患者被发现携带 DLG1-G344R。我们的结果表明，候选 PSD 基因中罕见的错义突变可能会增加对 SZ 和/或 ASD 的易感性。这些发现可能强化了这样的理论：罕见的非同义变异会给这些疾病带来巨大的遗传风险。
PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders.