CNTNAP2 variants affect early language development in the general population

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four‐marker haplotypes of rs2710102–rs759178–rs17236239–rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG, P = .0014). Our study suggests that common variants in the exon 13–15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.

[1]  C. Pennell,et al.  Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population , 2011, Genes, brain, and behavior.

[2]  Joseph T. Glessner,et al.  Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population. , 2010, The American journal of psychiatry.

[3]  P. Bolton,et al.  Traits Contributing to the Autistic Spectrum , 2010, PloS one.

[4]  D. Bishop.  Overlaps Between Autism and Language Impairment: Phenomimicry or Shared Etiology? , 2010, Behavior genetics.

[5]  C. Gillberg,et al.  Clinic attenders with autism or attention-deficit/hyperactivity disorder: cognitive profile at school age and its relationship to preschool indicators of language delay. , 2010, Research in developmental disabilities.

[6]  Thomas Haaf,et al.  Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder , 2010, neurogenetics.

[7]  Constance Scharff,et al.  FOXP2 as a molecular window into speech and language. , 2009, Trends in genetics : TIG.

[8]  D. Geschwind,et al.  A functional genetic link between distinct developmental language disorders. , 2008, The New England journal of medicine.

[9]  D. Geschwind.  Autism: Many Genes, Common Pathways? , 2008, Cell.

[10]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.

[11]  N. Marlow,et al.  Developmental assessment of preterm infants at 2 years: validity of parent reports , 2008, Developmental medicine and child neurology.

[12]  D. Geschwind,et al.  Genome-wide analyses of human perisylvian cerebral cortical patterning , 2007, Proceedings of the National Academy of Sciences.

[13]  D. Bishop,et al.  The broader language phenotype of autism: a comparison with specific language impairment. , 2007, Journal of child psychology and psychiatry, and allied disciplines.

[14]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[15]  R. Plomin,et al.  Genetic influences in different aspects of language development: the etiology of language skills in 4.5-year-old twins. , 2005, Child development.

[16]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[17]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[18]  Robert Plomin,et al.  Genetic influence on language delay in two-year-old children , 1998, Nature Neuroscience.

[19]  Donna J. Thal,et al.  Predicaments in early identification of specific language impairment: Does the early bird always catch the worm? , 1996 .

[20]  A. Couteur,et al.  Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders , 1994, Journal of autism and developmental disorders.

[21]  P. Twining,et al.  Effects of frequent ultrasound during pregnancy. , 1993, The Lancet.

[22]  F. Stanley,et al.  Effects of frequent ultrasound during pregnancy: a randomised controlled trial , 1993, The Lancet.

[23]  F. Stanley,et al.  Effects of frequent ultrasound during pregnancy: a randomised controlled trial. , 1993, Lancet.

[24]  S. Naidoo,et al.  Children with specific speech and language impairment , 1991 .

[25]  Jane Squires,et al.  The Effectiveness of Parental Screening of At-Risk Infants , 1989 .

[26]  J. Squires,et al.  The validity, reliability, and cost of a parent-completed questionnaire system to evaluate at-risk infants. , 1988, Journal of pediatric psychology.

[27]  Gerald Neligan Derek Prudham.  Norms for Four Standard Developmental Milestones by Sex, Social Class and Place in Family , 1969, Developmental medicine and child neurology.