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,
    • "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.
    Journal of Neural Transmission 11/2015; DOI:10.1007/s00702-015-1458-5 · 2.40 Impact Factor
    • "Although neuroanatomical anomalies in the MGN have not directly been examined in individuals with ASD, various lines of evidence using in vivo neuroimaging techniques have shown fundamental differences in the thalamus (as a whole), including reduced volume (Tamura, Kitamura, Endo, Hasegawa, & Someya, 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, Villalobos, Davies, Dahl, & Müller, 2006; Muller et al., 1998; Nair et al., 2013). In addition, CNTNAP2 and Cntnap2, respectively, also show expression in the thalamus of humans, nonhuman primates, and rodents (Abrahams et al., 2007; Alarcón et al., 2008; Hawrylycz et al., 2012; Kato et al., 2014; Lein et al., 2007) and brainstem structures including the cochlear nucleus (Han et al., 2014; Hawrylycz et al., 2012). Taken together, it could be that abnormalities in auditory processing observed in the ASD population are attributable to physiological anomalies in structures such as the cochlear nucleus in the brainstem and/or the MGN—structures subserving low-level processing of auditory information. "
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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
    Behavioral Neuroscience 10/2015; DOI:10.1037/bne0000096 · 2.73 Impact Factor
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    • "Although the number of causative genes for ASD could be more than 250, [Huguet et al., 2013] they affect a restricted number of biological pathways, including chromatin remodeling, mRNA translation and synaptic functions, [Toro et al., 2010; De Rubeis et al., 2013; Iossifov et al., 2014]. Among the synaptic genes associated with ASD, Ig-like cell adhesion molecules such as CNTN3 [Girirajan et al., 2011], CNTN4 [Fernandez et al., 2004] and CNTNAP2 [Alarcon et al., 2008; Arking et al., 2008] have important roles in neuronal interactions for synaptic targeting, neuronal migration, and axon guidance. Neurotrimin (NTM), which belongs to the same molecular family, is a glycosylphosphatidylinositol (GPI)-anchored cell adhesion protein and a member of the IgLON subfamily (containing also LAMP and OBCAM). "
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    ABSTRACT: Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37345 · 2.16 Impact Factor
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