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High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene

Molecular Psychiatry volume 15, pages 996–1005 (2010)Cite this article

Abstract

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.1 completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10−5). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect.

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Acknowledgements

We thank Dr Vlad Kustanovich at AGRE and Dr Sarah Spence formerly at AGRE for their support and guidance. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). AGRE Illumina HumanHap550 data were generated at the Children's Hospital of Philadelphia and the University of Pennsylvania through collaboration between the laboratories of Dr Hakon Hakonarson and Dr Maja Bucan. These data were provided to AGRE by Drs Bucan and Hakonarson. We thank them for their contribution. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by Grant MH64547 from the National Institute of Mental Health to Daniel H Geschwind (PI). This work was supported by MH64547, NS052108 and a grant from Cure Autism Now.

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Authors and Affiliations

  1. Department of Human Genetics, University of California, CA, Los Angeles, USA

    S P Strom, J L Stone, J R ten Bosch, B Merriman, R M Cantor, D H Geschwind & S F Nelson

  2. Center for Neurobehavioral Genetics, University of California, CA, Los Angeles, USA

    R M Cantor, D H Geschwind & S F Nelson

  3. Department of Psychiatry and Biobehavioral Sciences, University of California, CA, Los Angeles, USA

    R M Cantor, D H Geschwind & S F Nelson

  4. Department of Neurology, University of California, CA, Los Angeles, USA

    D H Geschwind

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  1. S P Strom
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  2. J L Stone
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Correspondence to S F Nelson.

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Strom, S., Stone, J., ten Bosch, J. et al. High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol Psychiatry 15, 996–1005 (2010). https://doi.org/10.1038/mp.2009.41

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