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. 2012 Dec 15;3(1):18.
doi: 10.1186/2040-2392-3-18.

Support for Calcium Channel Gene Defects in Autism Spectrum Disorders

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Free PMC article

Support for Calcium Channel Gene Defects in Autism Spectrum Disorders

Ake Tzu-Hui Lu et al. Mol Autism. .
Free PMC article

Abstract

Background: Alternation 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.

Methods: A 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.

Results: Four 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.

Conclusions: These associations support a role for common CCG SNPs in ASD.

Figures

Figure 1
Figure 1
Association analysis of genotyped and imputed SNPs in CACNA1C gene in (a) AGRE and (b) AGP samples. CACNA1C gene SNP associations showing the relative locations of the Timothy Syndrome mutation and the SNP with the strongest association in the AGRE sample (upper panel) and the AGP sample (lower panel).

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References

    1. Gotham K, Bishop SL, Lord C. In: Autism Spectrum Disorders: Chapter 2 Diagnosis of Autism Spectrum Disorders. Amaral DG, Dawson G, Geschwind DH, editor. New York: Oxford University Press; 2011.
    1. Autism and Developmental Disabilities Monitoring Network. 2007. http://www.cdc.gov/mmwr/pdf/ss/ss5601.pdf.
    1. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–1102. doi: 10.1001/archgenpsychiatry.2011.76. - DOI - PMC - PubMed
    1. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Magrini VJ, Ye K, Darnell JC, Darnell RB. et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–299. doi: 10.1016/j.neuron.2012.04.009. - DOI - PMC - PubMed
    1. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241. doi: 10.1038/nature10945. - DOI - PMC - PubMed
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