Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk lociReport as inadecuate

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Journal of Neurodevelopmental Disorders

, Volume 2, Issue 4, pp 210–223

First Online: 12 October 2010Received: 19 May 2010Accepted: 10 September 2010


Using behavioral and genetic information from the Autism Genetics Resource Exchange AGRE data set we developed phenotypes and investigated linkage and association for individuals with and without Autism Spectrum Disorders ASD who exhibit expressive language behaviors consistent with a motor speech disorder. Speech and language variables from Autism Diagnostic Interview-Revised ADI-R were used to develop a motor speech phenotype associated with non-verbal or unintelligible verbal behaviors NVMSD:ALL and a related phenotype restricted to individuals without significant comprehension difficulties NVMSD:C. Using Affymetrix 5.0 data, the PPL framework was employed to assess the strength of evidence for or against trait-marker linkage and linkage disequilibrium LD across the genome. Ingenuity Pathway Analysis IPA was then utilized to identify potential genes for further investigation. We identified several linkage peaks based on two related language-speech phenotypes consistent with a potential motor speech disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. While no compelling evidence of association was obtained under those peaks, we identified several potential genes of interest using IPA. Conclusion: Several linkage peaks were identified based on two motor speech phenotypes. In the absence of evidence of association under these peaks, we suggest genes for further investigation based on their biological functions. Given that autism spectrum disorders are complex with a wide range of behaviors and a large number of underlying genes, these speech phenotypes may belong to a group of several that should be considered when developing narrow, well-defined, phenotypes in the attempt to reduce genetic heterogeneity.

KeywordsAutism Linkage analysis Association analysis Motor Speech Disorder Autism genes Ingenuity Pathway Analysis IPA PPL-PPLD Electronic supplementary materialThe online version of this article doi:10.1007-s11689-010-9063-2 contains supplementary material, which is available to authorized users.

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Author: Judy F. Flax - Abby Hare - Marco A. Azaro - Veronica J. Vieland - Linda M. Brzustowicz


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