Our results suggest that variants in the exon 13–15 region of CNTNAP2
previously associated with deficits in SLI (Vernes et al. 2008
) and delayed language in autism (Alarcón et al. 2008
; Poot et al. 2010
) also affect the early stages of language development in children from the general population. This was a targeted hypothesis-driven study of a single gene, focusing on specific markers that have been strongly implicated in multiple prior reports of language-related disorder, rather than a genome-wide search for new variants.
The consistencies in findings across multiple investigations are noteworthy given several key differences in the natures of these studies. Alarcón et al. (2008)
studied probands with autism in an American sample, employing a parental report of language delay. Vernes et al. (2008)
assessed a UK sample, examined language test scores in older children and focused on families selected for SLI. In this study, we investigated an Australian sample, used a parental report measure assessing language development at age 2, and tested for association across the normal range. Despite the obvious differences in sample ascertainment and phenotypic characterization, there was agreement not only regarding the pattern of SNPs that were associated but also in the direction of allelic effects.
In our study, we constructed a single set of haplotypes using four neighboring markers in high LD which, based on the singlepoint pattern of results, appeared to form a core site of association. Although we did not genotype every associated marker from the Vernes et al. (2008)
study, these four markers were central to the nine-marker haplotypes that they previously assessed in SLI. Thus, our haplotypic alleles would be expected to capture much of the relevant variation from the earlier investigation. Indeed, haplotypic analyses from the two studies are generally concordant – both investigations found that the TTAA multimarker allele of rs2710102–rs759178–rs17236239–rs2538976 is associated with higher scores, whereas the alternative CGGG/CGAG alleles are associated with reduced performance (c.f. Table S4
of Vernes et al. 2008
). However, although the CGGG allele showed the strongest association in the SLI study, our analyses of the Raine sample identified much more significant effects for the rare CGAG combination, which here had particularly dramatic effects on language scores. These differences in haplotypic background could relate to the distinct population history of the samples. Regardless, the data suggest that in the vicinity of rs2710102–rs759178–rs17236239–rs2538976 there lie specific functional risk variants (as yet unidentified) with particular relevance to early language acquisition. Of note, the CNTNAP2
gene locus is one of the largest in the genome and could potentially contain multiple additional sites with functional relevance to neurodevelopmental phenotypes, to be clarified in future with high-density SNP screening and sequence-based strategies.
A methodological conclusion from our study is that a simple parental questionnaire focused on early language development can provide valuable phenotypic information for molecular genetic analyses, which may be particularly pertinent given the difficulties in directly assessing a child's performance in the earliest years of life. This is consistent with the core findings of Alarcón et al. (2008)
, who reported that rs2710102 and neighboring variants were associated with just a single item from the Autism Diagnostic Inventory – Revised (Lord et al. 1994
),‘age at first word’, in autistic probands. In addition, in a recent study of multiple traits contributing to the autistic spectrum, Steer et al. (2010)
reported a nominal association between rs17236239 and a factor they termed ‘language acquisition’, which primarily loaded on parental report measures of early language development. Our conclusion is also in line with the findings of Johnson et al. (2008)
, who showed good agreement between parent report and direct assessment of children's abilities at 2 years of age.
In terms of theoretical implications, it is clear that these common CNTNAP2
variants are not sufficient by themselves to account for language and communication disorders in children. This conclusion is in line with the current consensus that both SLI and autism are complex disorders resulting from the combined effect of multiple influences (Geschwind 2008
). We hypothesize that CNTNAP2
variants which usually yield only a small boost or lag in language acquisition will have more marked consequences when they occur in concert with other genetic or environmental risk factors. Bishop (2010)
suggests that autism may result from epistatic rather than additive interactions between genes. From this perspective, it would be of considerable interest to see whether there are additive or interactive effects of CNTNAP2
with genetic variants affecting social cognition, such as a recently described locus on chromosome 5p14 (St Pourcain et al. 2010