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Chunk #31 — ONLINE METHODS — BMD measurements and fracture definition — Stage 1 Genome-wide association analysis — Association analysis with BMD

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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
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each study performed genome-wide association analysis for FN-BMD and LS-BMD using sex-specific, age- weight- and principal components-adjusted standardized residuals analyzed under an additive (per allele) genetic model. Analyses of autosomal and chromosome X markers were done separately. Analysis of imputed genotype data accounted for uncertainty in each genotype prediction by using either the dosage information from MACH or the genotype probabilities from IMPUTE and BIM-BAM. Studies used MACH2QTL40 directly or via GRIMP41 (which uses genotype dosage value as a predictor in a linear regression framework), SNPTEST39, Merlin42, BIM-BAM or the linear mixed effects model of the Kinship and ProbABEL43 (Supplementary Tables 18D and 19D). For analysis of the X-chromosome either SNPTEST or R package was used in each participating study. We coded “effect allele homozygous genotype” as “2” and “other allele homozygous genotype” as “0” in the genotyped SNPs in men on the X chromosome. The imputed genotypes were coded as continuous variables from 0 to 2 to take into account imputation uncertainty. The genomic control method44 was used to correct the standard error (SE) by the square root of the genomic inflation factor (lambda): SEcorrected = SE × √lambda.