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Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders.

By Claudio Toma, Kerrie D. Pierce, Alex D. Shaw, Anna Heath, Philip B. Mitchell, Peter R. Schofield, Janice M. Fullerton

Posted 06 Jul 2018
bioRxiv DOI: 10.1101/363846 (published DOI: 10.1371/journal.pgen.1007535)

The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was 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 have also frequently been reported in autism, schizophrenia and other psychiatric or neurological disorders. We aim here to gain conclusive evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders by the comprehensive analysis of large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; iv) and conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). In a CNV mircroarray study, we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site in an extended BD family. Here we perform a quantitative-PCR validation showing imperfect segregation with disease (5 bipolar disorder relatives). 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 functional SNPs yield significant results in meta-analysis across psychiatric disorders. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. This large comprehensive candidate gene study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.

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