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

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Protocol publication

[…] SNPs were selected using several criteria, including linkage disequilibrium (LD) data from the Hapmap project and ability to develop a working genotyping assay. To perform the SNP selection, we first requested all possible dbSNP genotypes that will perform well in the Golden Gate assay per manufacturer’s guidelines (Illumina Inc., San Diego, CA). To maximize the amount of common variation tested while minimizing the number of markers typed, the software package Tagger was used to select a subset of these markers for genotyping such that the subset would cover the region of interest in the Hapmap (Build #21, July 2006) CEPH population with a minimum r2 value of 0.9. In total, 2042 SNPs were selected for genotyping in the region. Markers span 34.3Mb-47Mb on chromosome 17 (17q12-q21.33). 1975 SNPs meet the following criteria: Hardy-Weinberg Equilibrium P-Value ≥ 0.001, genotyping rate ≥ 85%, Mendelian Error Rate ≤ 1%. [...] Single SNPs were tested for association to ASD by performing a transmission disequilibrium test (TDT) using PLINK software. The PLINK TDT test computes a χ2 statistic to assess the presence and significance of transmission biases. The ‘--perm’ option was used to calculate an empiric p-value for each SNP based on an adaptive permutation model. In this model, SNPs found to be non-associated after a low number of tests are dropped while SNPs with higher initial association are tested by up to millions of permutations.To allow for haplotype analysis, groups of multiple markers were defined as haplotypes using the Four Gamete Test (FGT) implemented within Haploview, identifying 340 block intervals. This test robustly assesses whether a recombination has occurred between two markers in a population. Haplotype-based TDT testing within Haploview was performed to assess the transmission bias of the blocks defined by the FGT. […]

Pipeline specifications

Software tools Tagger, PLINK, Haploview
Databases dbSNP
Application GWAS
Chemicals Nucleotides, Histocompatibility Antigen H-2D