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

PLoS Genet. 2018 Dec 26;14(12):e1007535. doi: 10.1371/journal.pgen.1007535. eCollection 2018 Dec.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder / genetics
  • Bipolar Disorder / genetics
  • Craniofacial Abnormalities / genetics
  • DNA Copy Number Variations
  • Databases, Nucleic Acid
  • Epilepsies, Partial / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Introns
  • Male
  • Malformations of Cortical Development / genetics
  • Membrane Proteins / genetics*
  • Mental Disorders / genetics*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Schizophrenia / genetics
  • Sequence Deletion


  • CNTNAP2 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Cortical Dysplasia-Focal Epilepsy Syndrome

Grants and funding

This study was supported by the Australian National Medical and Health Research Council (NHMRC) Project Grants 1063960 and 1066177, and Program Grant 1037196. We gratefully acknowledge the Janette Mary O’Neil Research Fellowship (to JMF) and Mrs. Betty Lynch for supporting this work. DNA for the bipolar disorder family was extracted by Genetic Repositories Australia, an Enabling Facility that was supported by NHMRC Enabling Grant 401184. This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government. The authors report no biomedical financial interests or potential conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.