Bivariate association analysis of longitudinal phenotypes in families

Statistical genetic methods incorporating temporal variation allow for greater understanding of genetic architecture and consistency of biological variation influencing development of complex diseases. This study proposes a bivariate association method jointly testing association of two quantitative phenotypic measures from different time points. Measured genotype association was analyzed for single-nucleotide polymorphisms (SNPs) for systolic blood pressure (SBP) from the first and third visits using 200 simulated Genetic Analysis Workshop 18 (GAW18) replicates. Bivariate association, in which the effect of an SNP on the mean trait values of the two phenotypes is constrained to be equal for both measures and is included as a covariate in the analysis, was compared with a bivariate analysis in which the effect of an SNP was estimated separately for the two measures and univariate association analyses in 9 SNPs that explained greater than 0.001% SBP variance over all 200 GAW18 replicates.The SNP 3_48040283 was significantly associated with SBP in all 200 replicates with the constrained bivariate method providing increased signal over the unconstrained bivariate method. This method improved signal in all 9 SNPs with simulated effects on SBP for nominal significance (p-value <0.05). However, this appears to be determined by the effect size of the SNP on the phenotype. This bivariate association method applied to longitudinal data improves genetic signal for quantitative traits when the effect size of the variant is moderate to large.