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Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14

Abstract

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.

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Acknowledgements

We thank the patients with autism, and the family members who agreed to participate in this study, as well as the personnel of the CHG at DUMC, for their input on this project. We also thank Drs Robert Delong and Gordon Worley for referring patients and their families to the study. We thank the Translational Genomics Research Institute (TGen) for their generosity and effort in performing the Affymetrix chip assays. This research was supported, in part, by National Institutes of Health (NIH) program project Grant NS26630, and Grants R01 NS36768, R01 AG20135 and R01 NS42165; by the National Alliance of Autism Research (NAAR); and by a gift from the Hussman Foundation. The research conducted in this study complies with current US laws. We also gratefully acknowledge the resources provided by the AGRE consortium and the participating Autism Genetic Resource Exchange (AGRE) families. The AGRE is a program of Cure Autism Now (CAN). This work used the core resources of the GCRC (MO1 RR-00095) and the CHGR at VUMC and the CHG at DUMC.

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Correspondence to M A Pericak-Vance.

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Ma, D., Cuccaro, M., Jaworski, J. et al. Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14. Mol Psychiatry 12, 376–384 (2007). https://doi.org/10.1038/sj.mp.4001927

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