“High Density SNP Association Study of the 17q21 Chromosomal Region Linked to Autism Identifies CACNA1G as a Novel Candidate Gene”

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM[209850]) based on prior 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). Previously, Stone et al.1 completed a high-density SNP association study of 13.7Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here we extend this SNP-based association study to complete the coverage of the 2 LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. CONCLUSIONS: 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 for autism, these alleles do not contribute sufficient genetic effect to explain the observed linkage, indicating 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 previous studies of Chromosomes 5 and 7q3, suggest few if any major common risk alleles account for ASD risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify ASD genes, suggesting they should focus on identifying rare variants and common variants of small effect.