Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

Abstract

Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤−2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.

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Acknowledgements

Part of this work was supported by the Network in Europe on Male Osteoporosis (European Commission grant QL6-CT-2002-00491), by the Flemish Fund for Scientific Research (FWO Vlaanderen grants G.0331.02 and G.0662.07), by the Société Française de Rhumatologie (SFR) and by the French National Agency of Research (ANR).

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Correspondence to Aude Saint-Pierre.

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Supplementary Information accompanies the paper on European Journal of Human Genetics website

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Keywords

  • bivariate association
  • GWAS
  • BMD
  • osteoporosis

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