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

• Published in: Biological psychiatry (1969) 2011-05, Vol.69 (9), p.825-831
• Main Authors: Stein, Murray B, Yang, Bao-Zhu, Chavira, Denise A, Hitchcock, Carla A, Sung, Sharon C, Shipon-Blum, Elisa, Gelernter, Joel
• Format: Article
• Language: English
• Subjects: Adolescent; Adult and adolescent clinical studies; Alleles; Anxiety disorders; Anxiety disorders. Neuroses; autism; autism spectrum; behavioral inhibition; Biological and medical sciences; Child; Child clinical studies; Child, Preschool; childhood; Developmental disorders; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; genetics; Genotype; Haplotypes; Humans; Infantile autism; Linear Models; Male; Medical sciences; Membrane Proteins - genetics; Mutism - genetics; Nerve Tissue Proteins - genetics; Nervous system (semeiology, syndromes); Neurology; Odds Ratio; Phobia; Phobic Disorders - genetics; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Self Report; social anxiety; speech; Surveys and Questionnaires
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2010.11.008

Background 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. Methods 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. Results 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). Conclusions 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.