Constrained multivariate association with longitudinal phenotypes

Phillip E. Melton, Juan M. Peralta, Laura Almasy

The incorporation of longitudinal data into genetic epidemiological studies has the potential to provide valuable information regarding the effect of time on complex disease etiology. Yet, the majority of research focuses on variables collected from a single time point. This aim of this study was to test for main effects on a quantitative trait across time points using a constrained maximum-likelihood measured genotype approach. This method simultaneously accounts for all repeat measurements of a phenotype in families. We applied this method to systolic blood pressure (SBP) measurements from three time points using the Genetic Analysis Workshop 19 (GAW19) whole-genome sequence family simulated data set and 200 simulated replicates. Data consisted of 849 individuals from 20 extended Mexican American pedigrees. Comparisons were made among 3 statistical approaches: (a) constrained, where the effect of a variant or gene region on the mean trait value was constrained to be equal across all measurements; (b) unconstrained, where the variant or gene region effect was estimated separately for each time point; and (c) the average SBP measurement from three time points. These approaches were run for nine genetic variants with known effect sizes (>0.001) for SBP variability and a known gene-centric kernel (MAP4)-based test under the GAW19 simulation model across 200 replicates. When compared to results using two time points, the constrained method utilizing all 3 time points increased power to detect association. Averaging SBP was equally effective when the variant has a large effect on the phenotype, but less powerful for variants with lower effect sizes. However, averaging SBP was far more effective than either the constrained or unconstrained approaches when using a gene-centric kernel-based test. We determined that this constrained multivariate approach improves genetic signal over the bivariate method. However, this method is still only effective in those variants that explain a moderate to large proportion of the phenotypic variance but is not as effective for gene-centric tests.