title: Gene analysis for longitudinal family data using random-effects models.
abstract: We have extended our recently developed 2-step approach for gene-based analysis to the family design and to the analysis of rare variants. The goal of this approach is to study the joint effect of multiple single-nucleotide polymorphisms that belong to a gene. First, the information in a gene is summarized by 2 variables, namely the empirical Bayes estimate capturing common variation and the number of rare variants. By using random effects for the common variants, our approach acknowledges the within-gene correlations. In the second step, the 2 summaries were included as covariates in linear mixed models. To test the null hypothesis of no association, a multivariate Wald test was applied. We analyzed the simulated data sets to assess the performance of the method. Then we applied the method to the real data set and identified a significant association between FRMD4B and diastolic blood pressure (p-value = 8.3 × 10(-12)).
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Bruna
authors.initials: B
authors.lastname: Balliu
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands ; The Delft Bioinformatics Lab, Delft University of Technology, PO Box 5031, 2600 GA, Delft, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van den Akker
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Roula
authors.initials: R
authors.lastname: Tsonaka
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Uh