Computational protocol: Genome-wide meta-analysis of Psoriatic Arthritis Identifies Susceptibility Locus at REL

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Protocol publication

[…] We used GWAS datasets that passed stringent quality control filters for genotype imputation with Beagle () using HapMap phase 3 reference samples from the CEU, TSI, MEX and GJT collections, as well as for the subsequent statistical analyses. Low genomic control values for all three scans (German GWAS: λGC=1.01, CASP GWAS: λGC=1.02 and Canadian GWAS: λGC=1.03) indicated a minimal overall inflation of the test statistics due to population stratification.Power calculations were carried out using PS Power and Sample Size v3.0.12 () (). GWAS data were analyzed using R statistical environment version 2.10.0 and gPLINK v2.049 in combination with PLINK v1.05 ().We selected ten SNPs based on their P-value ranking for replication in two independent samples from Germany and Estonia comprising 252 PsA cases and 1,740 controls. All SNPs passed quality control measures which means that they had a high call rate (>95% in cases or controls), were not monomorphic (minor allele frequency >1% in cases or controls) and did not deviate from Hardy-Weinberg equilibrium in the control population (exact HWE P >10−4). Two of the ten follow-up SNPs were significantly associated with PsA and were therefore genotyped in four additional replication panels from the United States, Canada and Estonia.The Cochran-Mantel-Haenszel test was used for combined replication analysis of replication panel 1 and 2 from Germany and Estonia, in order to take the possibility of minor differing genetic backgrounds into account. The initial GWAS meta-analysis was performed using PLINK’s meta-analysis function with its standard error of odds ratio weighting option. Association results of replication panel 5 (CASP-DFU) were obtained with the statistical association test “Efficient Mixed-Model Association eXpedited” (EMMAX) to account for sample structure () and the combined replication analysis of all six replication panels as well as the combined GWAS-replication analysis was performed with METAL (). Logistic regression analysis to test for the independence of the two REL SNPs rs13017599 and rs702873 was performed with PLINK using the conditional analysis commands --logistic and --condition to test one SNP but adding the allelic dosage for the other SNP as a covariate. The conditional analysis was carried out for each cohort separately and results were subsequently combined by means of meta-analysis. […]

Pipeline specifications

Software tools PLINK, EMMAX
Application GWAS
Diseases Arthritis, Rheumatoid, Musculoskeletal Diseases, Psoriasis, Arthritis, Psoriatic