A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Is Associated with Increased Risk for Selective Mutism and Social Anxiety-Related Traits

Department of Psychiatry, University of California, San Diego, La Jolla, California 92093-0855, USA.
Biological psychiatry (Impact Factor: 10.26). 12/2010; 69(9):825-31. DOI: 10.1016/j.biopsych.2010.11.008
Source: PubMed


Selective mutism (SM), considered an early-onset variant of social anxiety disorder, shares features of impaired social interaction and communication with autism spectrum disorders (ASDs) suggesting a possible shared pathophysiology. We examined association of a susceptibility gene, contactin-associated protein-like 2 (CNTNAP2), for ASDs and specific language impairment with SM and social anxiety-related traits.
Sample 1 subjects were 99 nuclear families including 106 children with SM. Sample 2 subjects were young adults who completed measures of social interactional anxiety (n = 1028) and childhood behavioral inhibition (n = 920). Five single nucleotide polymorphisms in CNTNAP2 (including rs7794745 and rs2710102, previously associated with ASDs) were genotyped.
Analyses revealed nominal significance (p = .018) for association of SM with rs2710102, which, with rs6944808, was part of a common haplotype associated with SM (permutation p = .022). Adjusting for sex and ancestral proportion, each copy of the rs2710102*a risk allele in the young adults was associated with increased odds of being >1 SD above the mean on the Social Interactional Anxiety Scale (odds ratio = 1.33, p = .015) and Retrospective Self-Report of Inhibition (odds ratio = 1.40, p = .010).
Although association was found with rs2710102, the risk allele (a) for the traits studied here is the nonrisk allele for ASD and specific language impairment. These findings suggest a partially shared etiology between ASDs and SM and raise questions about which aspects of these syndromes are potentially influenced by CNTNAP2 and mechanism(s) by which these influences may be conveyed.

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    • "The Contactin Associated Protein-like 2 (CNTNAP2) gene, located on chromosome 7q, seems to be an interesting candidate gene due to its possible association with ASD in previous studies (Poot et al. 2011; Peñagarikano and Geschwind 2012; Rodenas-Cuadrado et al. 2014; Sampath et al. 2013; Toma et al. 2013; Anney et al. 2012; Arking et al. 2008; Li et al. 2010; Buxbaum 2009; Losh et al. 2008). Additionally , CNTNAP2 has been linked with language impairment (Arking et al. 2008; Alarcón et al. 2008; Poot et al. 2010; Stein et al. 2011). CNTNAP2 encodes CASPR2 with expression restricted to neurons. "
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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.
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    • "Regulation of neuronal migration and ASD 5 frequency in ASD patients ( Jackman et al. 2009 ; Elia et al. 2010 ; Mefford et al. 2010) . CNTNAP2 has been associated with abnormal social interactions as well as to language processing ( Stein et al. 2011 ; Whalley et al. 2011 ; Al - Murrani et al . 2012 ; Toma et al . "
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    • "rs2710102 , respectively . In rs2710102 , the genotypes of C / C , C / T , and T / T were used in some studies ( Whalley et al . , 2011 ; Whitehouse et al . , 2011 ; Zhou et al . , 2012 ; Clemm Von Hohenberg et al . , 2013 ; Sampath et al . , 2013 ) , and the genotypes of G / G , G / A , and A / A in an opposite strand were used in other studies ( Stein et al . , 2011 ; Ji et al . , 2013 ) . In this study , we used the genotypes of G / G , G / A , and A / A in rs2710102 ."
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    ABSTRACT: Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.
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