Testing cross-phenotype effects of rare variants in longitudinal studies of complex traits

• Type of Material: Article
• Authors: Prataydipta Rudra, Colorado School of Public Health; K. Alaine Broadaway, Emory University; Erin B. Ware, University of Michigan; Min A. Jhun, University of Michigan; Lawrence F. Bielak, University of Michigan; Wei Zhao, University of Michigan; Jennifer A. Smith, University of Michigan; Patricia A. Peyser, University of Michigan; Sharon L. R. Kardia, University of Michigan; Michael Epstein, Emory University; Debashis Ghosh, Colorado School of Public Health
• Language: English
• Date: 2018-06-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 WILEY PERIODICALS, INC.
• Final Published Version (URL): http://dx.doi.org/10.1002/gepi.22121
• Title of Journal or Parent Work: Genetic Epidemiology
• ISSN: 0741-0395
• Volume: 42
• Issue: 4
• Start Page: 320
• End Page: 332
• Grant/Funding Information: This work was supported by NIH grants GM117946, HG007508, HL054457, HL086694, HL119443, MH071537, and AR060893.
• Keywords: HYPERTENSION; gene mapping; GENE; REGRESSION; SIMILARITY; Genetics & Heredity; Science & Technology; rare variant; QUANTITATIVE TRAITS; LOCI; Mathematical & Computational Biology; RISK; HERITABILITY; pleiotropy; Life Sciences & Biomedicine; complex human traits; longitudinal data; GENOME-WIDE ASSOCIATION
• Research Categories: Health Sciences, Epidemiology; Biology, Biostatistics; Biology, Genetics

Abstract

Many gene mapping studies of complex traits have identified genes or variants that influence multiple phenotypes. With the advent of next-generation sequencing technology, there has been substantial interest in identifying rare variants in genes that possess cross-phenotype effects. In the presence of such effects, modeling both the phenotypes and rare variants collectively using multivariate models can achieve higher statistical power compared to univariate methods that either model each phenotype separately or perform separate tests for each variant. Several studies collect phenotypic data over time and using such longitudinal data can further increase the power to detect genetic associations. Although rare-variant approaches exist for testing cross-phenotype effects at a single time point, there is no analogous method for performing such analyses using longitudinal outcomes. In order to fill this important gap, we propose an extension of Gene Association with Multiple Traits (GAMuT) test, a method for cross-phenotype analysis of rare variants using a framework based on the distance covariance. The approach allows for both binary and continuous phenotypes and can also adjust for covariates. Our simple adjustment to the GAMuT test allows it to handle longitudinal data and to gain power by exploiting temporal correlation. The approach is computationally efficient and applicable on a genome-wide scale due to the use of a closed-form test whose significance can be evaluated analytically. We use simulated data to demonstrate that our method has favorable power over competing approaches and also apply our approach to exome chip data from the Genetic Epidemiology Network of Arteriopathy.