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Molecular Autism

, 3:18

First Online: 15 December 2012Received: 22 August 2012Accepted: 31 October 2012


BackgroundAlternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders ASD. Calcium channel genes CCG contribute to modulating neuronal function and evidence implicating CCG in ASD has been accumulating. We conducted a targeted association analysis of CCG using existing genome-wide association study GWAS data and imputation methods in a combined sample of parent-affected child trios from two ASD family collections to explore this hypothesis.

MethodsA total of 2,176 single-nucleotide polymorphisms SNP 703 genotyped and 1,473 imputed covering the genes that encode the α1 subunit proteins of 10 calcium channels were tested for association with ASD in a combined sample of 2,781 parent-affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange AGRE and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project AGP. SNP imputation using IMPUTE2 and a combined reference panel from the HapMap3 and the 1,000 Genomes Project increased coverage density of the CCG. Family-based association was tested using the FBAT software which controls for population stratification and accounts for the non-independence of siblings within multiplex families. The level of significance for association was set at 2.3E-05, providing a Bonferroni correction for this targeted 10-gene panel.

ResultsFour SNPs in three CCGs were associated with ASD. One, rs10848653, is located in CACNA1C, a gene in which rare de novo mutations are responsible for Timothy syndrome, a Mendelian disorder that features ASD. Two others, rs198538 and rs198545, located in CACN1G, and a fourth, rs5750860, located in CACNA1I, are in CCGs that encode T-type calcium channels, genes with previous ASD associations.

ConclusionsThese associations support a role for common CCG SNPs in ASD.

KeywordsAutism spectrum disorders Calcium channel genes Common variants Imputed SNPs Association studies AbbreviationsASDAutism spectrum disorders

ADI-RAutism Diagnostic Interview

CCGCalcium channel gene

FBATFamily Based Association Test

GWASGenome-wide Association Study

MDSMulti-dimensional scaling.

Electronic supplementary materialThe online version of this article doi:10.1186-2040-2392-3-18 contains supplementary material, which is available to authorized users.

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Autor: Ake Tzu-Hui Lu - Xiaoxian Dai - Julian A Martinez-Agosto - Rita M Cantor


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