Computational protocol: Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

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Protocol publication

[…] Linkage disequilibrium between SNPs was assessed using Haploview ( . DNA extracted from either whole blood or transformed lymphocyte cell lines was hybridized to the Illumina Infinium 610-Quad SNP array platform for whole genome genotyping at the McGill University and Génome Québec Innovation Centre. Genotyping was performed and stringent quality control measures were employed simultaneously in both cohorts, and the quality of SNP calls was deemed to be very high (0.004% discordance between replicate samples). SNPs were excluded from analysis in all cohorts if the call rate was <90%, if the minor allele frequency was <1%, or if the Mendelian error rate was >1%. For family-based studies, any marker displaying non-Mendelian inheritance was dropped from analysis for any family with the error. A detailed description of additional quality control measures can be found in Wright, et al . [...] For the primary study, family-based association testing of SNPs and haplotypes was performed using the PBAT module implemented within the Golden Helix HelixTree software package (Golden Helix, Inc. Bozeman, MT, USA; A sliding-window approach was employed to test the transmission of haplotypes composed of three adjacent SNPs (frequency >1%). A 2 Mb region was selected for haplotype testing as the number of possible unique haplotypes would be nearly equal to the number of SNPs tested in the initial analysis. Therefore, to be considered significant, a haplotype would have to reach the same Bonferroni-corrected threshold (or higher) that was set for SNPs in the initial analysis. An additive genetic model was applied under a null hypothesis of linkage and no association, and standard phenotypic residuals were used as offsets to increase the power of the test statistic. Bonferroni correction was applied by multiplying nominal P values by the total number of SNPs or haplotypes tested. The SNP association plot was generated using LocusZoom 1.0 ( case/control analyses, haplotypes were derived in the primary and replication populations using an expectation-maximization (EM) algorithm implemented in Golden Helix. Statistical analysis was performed in Stata10 (StataCorp, College Station, TX, USA). Comparison of MI status to the number of copies of haplotypes was performed using Fisher's exact test (using only subjects with haplotypes that could be determined with 100% posterior probability). Odds ratios comparing the odds of MI in subjects with 0, 1 or 2 copies of the chr8 haplotype, thus assuming an additive model, were estimated using logistic regression. For subjects with more than one haplotype assignment, EM probability estimates were used to weight haplotypes. For TSS subjects, parental and sibling genotypes were utilized when possible to resolve phase. For studies including siblings (TSS and CGS), empiric standard errors account for the possibility of sib-pair correlation . […]

Pipeline specifications

Software tools Haploview, PBAT, HelixTree, LocusZoom
Application GWAS
Organisms Mus musculus, Homo sapiens
Diseases Cystic Fibrosis, Intestinal Obstruction, Myocardial Infarction