Abstract
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.
Highlights
Alternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders (ASD)
Overall study design Using genome-wide association study (GWAS) data available to interested researchers and methods of imputation, a dense panel of 2,176 pruned common single-nucleotide polymorphisms (SNP) (703 called and 1,473 imputed) in 10 Calcium channel genes (CCG) was tested for association with ASD using the Family Based Association Test (FBAT) software that corrects for population stratification and non-independence of parent/child trios within nuclear families
Most encouraging is the association of rs108486653, an imputed SNP within the CACN1C gene which encodes Cav1.2, a subunit of a calcium channel that is expressed predominantly in neurons and cardiac pacemaker cells
Summary
Alternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders (ASD). ASD prevalence is currently estimated at 1/88 children (http://www.cdc.gov/media/ releases/2012/p0329_autism_disorder.html), with a 4:1 ratio of boys to girls [2]. A recent twin study indicates that ASD is heritable, but its etiology is likely to include both genetic and environmental factors and their interactions [3]. All studies indicate that the etiology of ASD is likely to be very heterogeneous, and most predisposing genetic and environmental risk factors are currently unidentified. Recent whole-genome exon sequencing studies of ASD samples estimate that as many as 100 to 1,000 genes may be involved [4]. We report an association study that examines the family of calcium channel genes (CCG) that is supported by: (1) biologic insights into the roles of these genes in the brain [7]; (2) evidence derived from a Mendelian disorder that features ASD [8]; and (3) several previous more limited linkage and association studies of ASD
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