title: Defining the contribution of CNTNAP2 to autism susceptibility.
abstract: Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, p = 2.0 x 10(-4); rs2215798, p = 1.6 x 10(-4)) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (r (2) = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, p = 9.0 x 10(-6); rs2253031, p = 2.5 x 10(-5)). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of CNTNAP2 gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (p = 1.9 x10(-5)). Consequently, this study suggests that although CNTNAP2 dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited.
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetics Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.forename: Shambu
authors.initials: S
authors.lastname: Bhat
authors.forename: Simone
authors.initials: S
authors.lastname: Gupta
authors.forename: Ashley
authors.initials: A
authors.lastname: O'Connor
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins