Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders
Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders
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DOI：
10.1371/journal.pgen.1007535
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发表时间：
2018-12-01
期刊：
影响因子：
4.5
通讯作者：
Fullerton, Janice M.
中科院分区：
文献类型：
--
作者：
Toma, Claudio;Pierce, Kerrie D.;Fullerton, Janice M.
接触素相关蛋白样2（CNTNAP 2）基因是neurexin超家族的成员。CNTNAP 2首先与皮质发育不良-局灶性癫痫（CDFE）综合征有关，这是一种以智力残疾、癫痫、语言障碍和自闭症特征为特征的隐性疾病。随后在自闭症、精神分裂症和其他精神或神经疾病中报道了CNTNAP 2中相关的SNP和杂合缺失。我们的目的是通过分析大型基因组数据集中的多类遗传变异，全面研究CNTNAP 2在精神疾病易感性中的作用的证据。在这项研究中，我们使用：i）来自精神病基因组学联盟（PGC）GWAS的七种精神疾病的汇总统计; ii）检查患者和对照中所有报告的CNTNAP 2结构变体; iii）进行功能性或先前相关SNP的交叉疾病分析;和iv）使用测序数据对致病性罕见变体进行负荷测试（4，483例ASD和6，135例精神分裂症病例，以及13，042例对照）。来自先前报道的精神病病例中CNTNAP 2的CNV分布与基因组变异数据库的对照没有区别。基于基因的关联测试并不涉及自闭症、精神分裂症或其他精神病表型的常见变异。建议的功能SNPs rs7794745和rs 2710102的关联，据报道会影响大脑连接，没有被复制;预测的功能SNPs也没有在SNP水平或基因水平的精神疾病荟萃分析中产生显着的结果。与对照组相比，自闭症或精神分裂症患者的CNTNAP 2罕见变异负荷并不高。最后，在一个扩展的双相情感障碍家族的CNV微阵列研究中，有5个受影响的亲属，我们以前确定了CNTNAP 2内含子1中的131 kb缺失，去除了FOXP 2转录因子结合位点。定量PCR验证和分离分析显示，这种CNV与BD分离不完善。这项大型综合性研究表明，CNTNAP 2可能不是一个强大的风险基因的精神病表型。
The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders. We aimed to comprehensively examine evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders, by the analysis of multiple classes of genetic variation in large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS for seven psychiatric disorders; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; and iv) conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did predicted functional SNPs yield significant results in meta-analysis across psychiatric disorders at either SNP-level or gene-level. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. Finally, in a CNV mircroarray study of an extended bipolar disorder family with 5 affected relatives we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site. Quantitative-PCR validation and segregation analysis of this CNV revealed imperfect segregation with BD.This large comprehensive study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.