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. 2010 Oct;15(10):996-1005.
doi: 10.1038/mp.2009.41. Epub 2009 May 19.

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

S P Strom  1 , J L Stone, J R Ten Bosch, B Merriman, R M Cantor, D H Geschwind, S F Nelson
Affiliations

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

S P Strom et al. Mol Psychiatry. 2010 Oct.

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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Figures

Figure 1
Figure 1. Single marker Association Results
Individual SNP transmission biases from 284 Male-Only autism trios are plotted as -Log10 of the empiric P-Value versus genomic position in mega-bases (Mb). Local significance threshold is represented by a black dotted line. Two markers (filled triangles) out of 1975 markers tested are associated at a locally significant level, adjacent SNPs within CACNA1G.
Figure 2
Figure 2. Single marker Association Results for CACNA1G
Individual SNP transmission biases from 284 Male-Only autism trios of markers within the genetic interval containing the CACNA1G gene are plotted as -Log10 of the empiric P-Value versus genomic position in mega-bases (Mb). Local significance threshold is represented by a black dotted line. Two markers (rs757415 and rs12603112; filled triangles) are associated at a locally significant level. A gene diagram representing exons (blue rectangles), introns (blue lines), and direction of transcription (blue arrowheads) is included for reference.
Figure 3
Figure 3. Haplotype Association Results
Haplotype transmission biases from 284 Male-Only autism trios are plotted as -Log10 of the P-Value versus genomic position in mega-bases (Mb). For each block locus, only the block with the most significant P-Value is plotted. Nominal local significance threshold (P-Value ≤ 0.001) is represented by a black dotted line. One haplotype (circled) are associated at this nominal level. This block contains the two individual SNPs found to be associated at a locally significant level.
Figure 4
Figure 4. Linkage Disequilibrium Status of SNPs within CACNA1G
Haplotypes estimated from 284 Male-Only autism trios using the Four Gamete Test (FGT) are plotted as a function of D‘. Approximate location of CANCA1G in relation to the markers is represented by the UCSC Genome Browser track at the top of the figure. Block 3 (highlighted in blue) is the block most associated with Autism Spectrum Disorder in this study (P-Value -5).
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