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Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs
M Alarcón1, A L Yonan, T C Gilliam
1Department of Neurology, UCLA School of Medicine, Center for Neurobehavioral Genetics and Neuropsychiatric Research Institute, Los Angeles, CA, USA. malarcon@ucla.edu
Molecular Psychiatry
|April 13, 2005
Summary
This study identified novel autism susceptibility loci on chromosomes 3q and 17q associated with early language development. These findings highlight the utility of endophenotypes in autism genetics research.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Pediatrics
Background:
- Autism is a neurodevelopmental syndrome characterized by deficits in language, social skills, and repetitive behaviors.
- Endophenotypes, such as specific behavioral traits, may offer greater statistical power for genetic linkage analysis compared to the overall autism diagnosis.
- Previous research identified a quantitative trait locus (QTL) for spoken language on chromosome 7q35 in families with autism.
Purpose of the Study:
- To conduct a genome-wide scan for autism endophenotypes in a larger cohort of multiplex families.
- To identify novel genetic loci associated with early language development in autism.
- To investigate potential heterogeneity within the autism sample and its impact on linkage findings.
Main Methods:
- A nonparametric quantitative trait locus (QTL) genome scan was performed on 291 multiplex families with autism.
- Analysis focused on endophenotypes including 'age at first word' and 'age at first phrase'.
- Ordered-Subsets Analysis was used to explore potential heterogeneity on chromosome 7.
Main Results:
- The strongest evidence for an 'age at first word' QTL was found on chromosomes 3q (Z=3.10, P<0.001) and 17q (Z=2.84, P=0.002), representing novel susceptibility loci.
- Support was found for a previously identified locus on chromosome 17q (Z=2.22, P=0.013) associated with 'age at first phrase'.
- The linkage peak on 7q35 was attenuated in the larger sample, with Ordered-Subsets Analysis suggesting specific subgroups drive this signal.
Conclusions:
- Novel autism endophenotype susceptibility loci for early language development were identified on chromosomes 3q and 17q.
- The 7q35 locus may harbor genes influencing spoken language variability, not exclusively related to language delay in autism.
- Utilizing endophenotypes enhances the power to detect genetic contributions to autism spectrum disorder.