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.
Highlights
Autism (MIM 209850) is a highly heritable, early onset childhood neuropsychiatric developmental disorder characterized by impairments in the three core domains of social interaction and communication, language development, and repetitive restricted behavior and interests
The existing view of the genetic architecture of autism is that numerous genes are involved, but we do not have enough evidence to distinguish between simple heterogeneity and multigenic inheritance
It is generally believed that different types of sequence variants impart quantitatively different genetic risks and are, enriched in different types of families: for example, multiplex families are enriched for rare variants of large effect [62,63] whereas simplex families harbor common variants of small effect [64] or de novo mutations [65,66,67]
Summary
Autism (MIM 209850) is a highly heritable, early onset childhood neuropsychiatric developmental disorder characterized by impairments in the three core domains of social interaction and communication, language development, and repetitive restricted behavior and interests. Numerous gene discovery studies have implicated a small number of genes with either rare highly-penetrant mutations, or low-penetrant common variants or copy-number variants (CNV) that together explain no more than 15-30% of the population prevalence [8,9,10,11,12] These studies have implicated many genes of diverse function, the underlying genetic heterogeneity ensures that no single gene accounts for the majority of autism. Mice lacking CNTNAP2 show striking similarity to the core deficits of behavioral and cognitive functions that are seen in patients with ASD signifying its vital role in brain development [32] This gene was first identified in autism by linkage in a Old Order Amish family with an autosomal recessive founder null mutation leading to cortical dysplasia-focal epilepsy (CDFE; MIM 610042) characterized by the presence of neuronal migration abnormalities, seizures, intellectual disability, language regression, hyperactivity, impulsive and aggressive behavior, and ASD [33]. It remains entirely possible that CNTNAP2 harbors a diversity of coding and noncoding mutations that will be important for understanding autism and ASD pathophysiology, but its epidemiological impact is small
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