Computational protocol: Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

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Protocol publication

[…] A further 4,330 EC cases and 26,849 female controls were genotyped as part of the Endometrial Cancer Association Consortium (ECAC), with samples from seven countries: UK, USA, Belgium, Germany, Norway, Sweden and Australia. The controls were selected from healthy females participating in the Breast Cancer Association Consortium (BCAC) and Ovarian Cancer Association Consortium (OCAC) part of the iCOGS project and matched and analysed with cases in eight groups by geographical location (see ). These samples were genotyped using a custom Illumina Infinium iSelect array with 211,155 SNPs designed by the COGS (Collaborative Oncological Gene-environment Study) initiative. The SNPs on this array were chosen based on regions of interest from previous breast, prostate, ovarian and endometrial cancer studies, rather than on genome-wide coverage. We did not impute genotypes from the COGS studies, but included directly-genotyped SNPs in the discovery meta-analysis. These SNPs were not used for locus fine mapping. [...] Whole-genome imputation using two reference panels (1000 Genomes 2012 release and 196 high-coverage whole genome-sequenced UK individuals) was performed with IMPUTE2, yielding up to 6 million SNPs either typed or imputed with high quality (info score >0.9). Case-control analysis for each GWAS data set was performed using frequentist tests with a logistic regression model using SNPTEST (v2.4). There was no evidence of systematic over-dispersion of the test statistic for any of the 16 studies (lambdaGC = 1.01–1.04 based on weakly correlated SNPs, r2 < 0.2). Fixed-effects, inverse variance weighted meta-analysis was conducted for the 6 million well-imputed SNPs in the eight CRC and EC GWAS (8,935 cases, 13,396 controls) across the genome using GWAMA (v2.1). For the ~200,00 SNPs genotyped on the COGS array, the additional 4,330 EC cases and 26,849 controls from ECAC were included in a meta-analysis of 16 studies yielding a total of 13,265 cases and 40,245 controls for these loci. SNPs with globally significant CRC/EC associations (Pmeta < 5 × 10−8) were identified and the regions examined using standard fine mapping and annotation methods. […]

Pipeline specifications

Software tools IMPUTE, SNPTEST, GWAMA
Application GWAS
Diseases Autoimmune Diseases, Neoplasms, Colorectal Neoplasms, Endometrial Neoplasms