Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene

UCLA Center for Autism Research and Treatment, Semel Institute of Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2008; 82(1):150-9. DOI: 10.1016/j.ajhg.2007.09.005
Source: PubMed


Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.

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Available from: Maricela Alarcón
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    • "Many of these studies have focused on ASD, and using linkage and genome-wide association studies (GWAS) as well as copy number variation (CNV) analyses have clearly associated between Caspr2 and ASD (Alarcon et al., 2008; Arking et al., 2008; Bakkaloglu et al., 2008; Li et al., 2010; O'Roak et al., 2011). Additionally, common variants in Caspr2 have also been associated with ASD (Anney et al., 2012; Arking et al., 2008; Stein et al., 2011). "
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    ABSTRACT: Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name Cntnap2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (Cntnap2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock-in reporter line (Cntnap2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD.
    Full-text · Article · Dec 2015 · Molecular and Cellular Neuroscience
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    • "The noncoding variant, rs7794745 (T/A, presumed risk allele T) was found to associate with an increased risk for ASD (Arking et al. 2008; Sampath et al. 2013). Other intronic SNPs, such as rs2710102, have been identified to be associated with the quantitative autism endophenotypes of age-at-first word (p = 0.0006) (Alarcón et al. 2008) and specific language impairment (p = 0.002–5 9 10 -5 ) (Vernes et al. 2008) (C/T, presumed risk allele C). Both SNPs are located on chromosome 7, rs7794745 is located at intron 2 (chr7:146489606; GRCh37.p13), and rs2710102 is located at intron 13 (chr7:147574390; GRCh37.p13). "
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    ABSTRACT: The Contactin Associated Protein-like 2 (CNTNAP2) gene has been discussed to be associated with different symptoms of autism spectrum disorders (ASDs) and other neurodevelopmental disorders. We aimed to elucidate the genetic association of CNTNAP2 within high functioning ASD (HFA), focusing on autism specific symptoms and reducing intelligence related factors. Furthermore, we compared our findings conducting a meta-analysis in patients with ASD and HFA only. A case-control association study was performed for HFA (HFA, n = 105; controls, n = 133). Moreover, we performed a family-based association study (DFAM) analysis (HFA, n = 44; siblings, n = 57). Individuals were genotyped for the two most frequently reported single nucleotide polymorphisms (SNPs) in the CNTNAP2 gene (rs2710102, rs7794745). Furthermore, a meta-analysis using the MIX2 software integrated our results with previously published data. A significant association for the carriers of the T-allele of the rs7794745 with HFA was found in the case-control sample [OR = 1.547; (95 % CI 1.056-2.266); p = 0.025]. No association could be found by DFAM with any of the CNTNAP2 SNPs with HFA. The meta-analysis of both SNPs did not show a significant association with either ASD or with HFA. Overall, including case-control, sibs, and meta-analysis, we could not detect any significant association with the CNTNAP2 gene and HFA. Our results point in the direction that CNTNAP2 may not play a major role in HFA, but rather seems to have a significance in neurodevelopmental disorders or in individuals displaying intellectual delays.
    Full-text · Article · Nov 2015 · Journal of Neural Transmission
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    • "Changes in the thalamus have been observed in the ASD population, including reduced volume (Tamura et al., 2010;Tsatsanis et al., 2003), altered neurochemical composition (Friedman et al., 2003), and abnormal thalamocortical connectivity (Cheon et al., 2011;Chugani et al., 1997;Mizuno et al., 2006;Muller et al., 1998;Nair et al., 2013), suggesting that the thalamus may play a role in the behavioral etiology of ASD symptoms. CNTNAP2 expression is also present in the thalamus of both humans, nonhuman primates, adult mice, and zebra finch (Alarcón et al., 2008;Han et al., 2014;Hawrylycz et al., 2012;Kato et al., 2014;Lein et al., 2007;Panaitof et al., 2010). A reduction in the number of neurons in the MGN could significantly alter thalamocortical/corticothalamic connectivity and function, ultimately resulting in fewer reciprocal projections to and from the cortex. "
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    ABSTRACT: Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder. (PsycINFO Database Record
    Full-text · Article · Oct 2015 · Behavioral Neuroscience
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