Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene

Abstract

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.

Shining a light on CNTNAP2: complex functions to complex disorders

“…During human brain development, its expression is highest in frontal and anterior lobes, striatum and dorsal thalamus. 18,40 This expression pattern recapitulates the cortico-striato-thalamic circuitry known to modulate higher order cognitive functions, including speech and language, reward, and frontal executive function. In the human cortex, CNTNAP2 is expressed in layers II-V 10 with enrichment in Broca's area and other perisylvian brain regions.…”

“…5,18,19 An intron 3 deletion containing no known functional elements was identified in a schizophrenia patient who presented with seizures, but normal language. 5 A deletion within intron 1 was reported in two independent patients suffering from ASD, ID and dysarthric language 18 and from ADHD, 19 respectively. Intron 1 contains a regulatory element bound by the FOXP2 transcription factor.…”

“…CNTNAP2 variants are associated with complex disorders Genome-wide association studies have also linked CNTNAP2 to complex neurological disorders, including language impairment, autism, dyslexia, schizophrenia, and depression 18,20,[22][23][24][25][26] (Table 2), although causal variants have not yet been identified. Convincing evidence has linked common variants (ie, single nucleotide polymorphisms; SNPs) in the CNTNAP2 region with the most common form of language disorder in children: specific language impairment (SLI).…”

“…Shining a light on CNTNAP2 P Rodenas-Cuadrado et al increased familial risk for autism with a SNP in intron 2 of the CNTNAP2 gene (rs7794745). 23 Independent studies have highlighted significant association between other SNPs and language endophenotypes of ASD, including age at first word (rs2710102) 18 and age at first phrase (rs1718101). 22 Interestingly, a subset of the cluster of SNPs in intron 13-14 (rs2710102; rs759178; rs17236239; rs2538976) have been associated with early communicative behaviour in a large screen of phenotypically normal individuals, 28 suggesting that genetic variance at this locus may have a role in individual differences in the general Not specified Not specified Not specified N407S 1 (N ¼ 635) 10 Not specified Not specified Not specified N418D 1 (N ¼ 635) 10 Not specified Not specified Not specified Y716C 1 (N ¼ 635) 10 Not specified Not specified Not specified G731S (conserved) 1 (N ¼ 635) 10 Not specified Not specified Not specified I869T (predicted deleterious) Four probands, three families (N ¼ 635) 10 Not specified Not specified Not specified R906H 2 (N ¼ 635) 10 Not specified Not specified Not specified R1119H (predicted deleterious) 2 (N ¼ 635) 10 Not specified Not specified Not specified D1129H (predicted deleterious) 2 (N ¼ 635) 10 Not specified Not specified Not specified A1227T 2 (N ¼ 635) 10 Not specified Not specified Not specified I1253T (predicted deleterious) 2 (N ¼ 635) 10 Not specified Not specified Not specified T1278I (predicted deleterious) 2 (N ¼ 635) 10 Not specified Shining a light on CNTNAP2 P Rodenas-Cuadrado et al population.…”

“…41 Other sensory responses such as acoustic and olfactory were not impaired. 41 Given the link between CNTNAP2, autism and social communication, 10,18,28 it is intriguing to note that mutant mice displayed increased stereotyped and repetitive behaviour, and spent less time engaging in social play. 41 Hence, the use of animal models, such as described herein, allow a controlled exploration of the cellular and neurobiological effects of CASPR2 loss.…”