A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Increases Familial Risk of Autism

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2008; 82(1):160-4. DOI: 10.1016/j.ajhg.2007.09.015
Source: PubMed


Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.

Download full-text


Available from: Dan E Arking, Dec 05, 2014
1 Follower
29 Reads
  • Source
    • "Genetics has already informed pharmacological treatment exploration for ASD ( Jeste and Geschwind, 2014). For example , CNTNAP2 variants have been associated with ASD and other neurodevelopmental disorders (Alarcon et al., 2008; Arking et al., 2008); this variant has been shown to have increased expression in frontostriatal circuits of the brain (Abrahams et al., 2007). CNTNAP2-mutant mouse models, which present ASD-like symptoms, have shown alleviated repetitive behaviors, but no change in social deficits when treated with risperidone, a dopamine antagonist (Penagarikano et al., 2011; Penagarikano and Geschwind, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.
    Omics: a journal of integrative biology 04/2015; 19(4):197-208. DOI:10.1089/omi.2015.0020 · 2.36 Impact Factor
  • Source
    • "Given this, many molecular genetic studies have questioned whether ASC is associated with specific genetic variants associated with language impairment, for example CNTNAP2 [e.g. Alarcó n et al., 2008; Arking et al., 2008], FOXP2 [e.g. Newbury et al., 2002], and SHANK3 [Durand et al., 2007]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by ∼3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation = −0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation = 0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2014; 165(7). DOI:10.1002/ajmg.b.32262 · 3.42 Impact Factor
  • Source
    • "This study initiated a wave to identify rare mutations in synaptic genes and it also gave rise to a general concept of ''synaptopathy'' that suggests synaptic plasticity is an important etiology not only for ASD, but also for neuropsychiatry disorders in general such as schizophrenia and Alzheimer disorder [40] [41] [42]. Other well-established ASD genes include SHANK3 [43], CNTN4 [44], CNTNAP2 [45], NRXN1 [46], and OXTR [47] [48]. 4. Genome-wide association study (GWAS) GWAS is a powerful data driven approach to identify, without prior knowledge, common variants with low penetrance. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.
    Biochemical and Biophysical Research Communications 09/2014; 452(2). DOI:10.1016/j.bbrc.2014.08.108 · 2.30 Impact Factor
Show more