Characterization of direct and/or indirect genetic associations for multiple traits in longitudinal studies of disease progression

Abstract

When quantitative longitudinal traits are risk factors for disease progression and subject to random biological variation, joint model analysis of time-to-event and longitudinal traits can effectively identify direct and/or indirect genetic association of single nucleotide polymorphisms (SNPs) with time-to-event. We present a joint model that integrates: i) a multivariate linear mixed model describing trajectories of multiple longitudinal traits as a function of time, SNP effects, and subject-specific random effects, and ii) a frailty Cox survival model that depends on SNPs, longitudinal trajectory effects, and subject-specific frailty accounting for dependence among multiple time-to-event traits. Motivated by complex genetic architecture of type 1 diabetes complications (T1DC) observed in the Diabetes Control and Complications Trial (DCCT), we implement a two-stage approach to inference with bootstrap joint covariance estimation and develop a hypothesis testing procedure to classify direct and/or indirect SNP association with each time-to-event trait. By realistic simulation study, we show that joint modelling of two time-to-T1DC (retinopathy, nephropathy) and two longitudinal risk factors (HbA1c, systolic blood pressure) reduces estimation bias in genetic effects and improves classification accuracy of direct and/or indirect SNP associations, compared to methods that ignore within-subject risk factor variability and dependence among longitudinal and time-to-event traits. Through DCCT data analysis, we demonstrate feasibility for candidate SNP modelling, and quantify effects of sample size and Winners curse bias on classification for two SNPs identified as having indirect associations with time-to-T1DC traits. Overall, joint analysis of multiple longitudinal and multiple time-to-event traits provides insight into complex trait architecture.