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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    • "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). Numerous mutations in Caspr2 have been identified, in many different regions of the protein, both intra-and extra-cellularly, and have been associated with ASD (Bakkaloglu et al., 2008). "
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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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