Computational protocol: Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

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Protocol publication

[…] Genome-wide association analysis was performed using the GenABEL package in R . A score test was used to test for association between the age- and sex-adjusted residuals of sphingolipid traits (both as absolute concentrations and as relative content of the total sphingolipid pool: mol%) and SNP genotypes using an additive model. The Genomic Control procedure was used to account for under-estimation of the standard errors of effects, which occurs because of pedigree structure present in the data . For the most interesting results and the species ratios, we re-analysed the data using “mmscore” function, a score test for family-based association , as implemented in GenABEL. The relationship matrix used in analysis was estimated using genomic data with “ibs” (option weight = “freq”) function of GenABEL. This analysis, accounting for pedigree structure in an exact manner, allowed for unbiased estimation of the effects of the genetic variants (adjusted for age and sex). The results from all cohorts were combined into a fixed-effects meta-analysis with reciprocal weighting on standard errors of the effect-size estimates, using MetABEL ( Thresholds for genome wide significance were set at a p value of less than 1.57×10−7 (0.05/318,237 SNPs) for the individual populations. For the overall meta-analysis we chose to use the conservative threshold of 7.2×10−8 . Since many of the traits tested and especially the ratios demonstrate high degrees of correlation, introducing a suitable statistical correction the multiple testing of the 76 correlated traits would be complex. Since Bonferroni correction (unsuitable in this instance) would lower thresholds to values between p = 10−9 to 10−10, and since all five genomic regions have variants with p values <10−10, we report the age-sex corrected p values alone. The threshold for replication of significant results from one population in other cohorts was set at a p-value less than 0.05 divided by the number of SNPs tested. All significant variants reported are in Hardy-Weinberg Equilibrium, and effect directions are consistent across all five populations. […]

Pipeline specifications

Software tools GenABEL, MetABEL
Application GWAS
Diseases Diabetes Mellitus, Cardiomyopathies, Myocardial Infarction, Pancreatitis, Atherosclerosis