Mixed-effects models for GAW18 longitudinal blood pressure data

Abstract

In this paper, we propose two mixed-effects models for Genetic Analysis Workshop 18 (GAW18) longitudinal blood pressure data. The first method extends EMMA, an efficient mixed-model association-mapping algorithm. EMMA corrects for population structure and genetic relatedness using a kinship similarity matrix. We replace the kinship similarity matrix in EMMA with an estimated correlation matrix for modeling the dependence structure of repeated measurements. Our second approach is a Bayesian multiple association-mapping algorithm based on a mixed-effects model with a built-in variable selection feature. It models multiple single-nucleotide polymorphisms (SNPs) simultaneously and allows for SNP-SNP interactions and SNP-environment interactions. We applied these two methods to the longitudinal systolic blood pressure (SBP) and diastolic blood pressure (DBP) data from GAW18. The extended EMMA method identified a single SNP on Chr5:75506197 (p-value = 4.67 × 10-7) for SBP and three SNPs on Chr3:23715851 (p-value = 9.00 × 10-8), Chr 17:54834217 (p-value = 1.98 × 10-7), and Chr21:18744081 (p-value = 4.95 × 10-7) for DBP. The Bayesian method identified several additional SNPs on Chr1:17876090 (Bayes factor [BF] = 102), Chr3:197469358 (BF = 69), Chr15:87675666 (BF = 43), and Chr19:41642807 (BF = 33) for SBP. Furthermore, for SBP, we found a single SNP on Chr3:197469358 (BF = 69) that has a strong interaction with age. We further evaluated the performances of the proposed methods by simulations.