Powerful and robust cross-phenotype association test for case-parent trios

• Type of Material: Article
• Authors: S. Taylor Fischer, Emory University; Yunxuan Jiang, Emory University; K. Alaine Broadaway, Emory University; Karen Conneely, Emory University; Michael Epstein, Emory University
• Language: English
• Date: 2018-07-01
• 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.22116
• Title of Journal or Parent Work: Genetic Epidemiology
• ISSN: 0741-0395
• Volume: 42
• Issue: 5
• Start Page: 447
• End Page: 458
• Grant/Funding Information: This work was supported by NIH grants GM117946 and HG007508.; The data [and samples] from the GoKinD study were supplied by the NIDDK Central Repositories.; The Genetics of Kidneys in Diabetes (GoKinD) Study was conducted by the GoKinD Investigators and supported by the Juvenile Diabetes Research Foundation, the CDC, and the Special Statutory Funding Program for Type 1 Diabetes Research administered by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
• Keywords: RARE; QUANTITATIVE TRAITS; FAMILY-BASED ASSOCIATION; Mathematical & Computational Biology; Genetics & Heredity; PLEIOTROPY; genetic association testing; DIABETIC-NEPHROPATHY; case-parent trio design; pleiotropy; Life Sciences & Biomedicine; Science & Technology
• Research Categories: Biology, Genetics; Biology, Biostatistics

Abstract

There has been increasing interest in identifying genes within the human genome that influence multiple diverse phenotypes. In the presence of pleiotropy, joint testing of these phenotypes is not only biologically meaningful but also statistically more powerful than univariate analysis of each separate phenotype accounting for multiple testing. Although many cross-phenotype association tests exist, the majority of such methods assume samples composed of unrelated subjects and therefore are not applicable to family-based designs, including the valuable case-parent trio design. In this paper, we describe a robust gene-based association test of multiple phenotypes collected in a case-parent trio study. Our method is based on the kernel distance covariance (KDC) method, where we first construct a similarity matrix for multiple phenotypes and a similarity matrix for genetic variants in a gene; we then test the dependency between the two similarity matrices. The method is applicable to either common variants or rare variants in a gene, and resulting tests from the method are by design robust to confounding due to population stratification. We evaluated our method through simulation studies and observed that the method is substantially more powerful than standard univariate testing of each separate phenotype. We also applied our method to phenotypic and genotypic data collected in case-parent trios as part of the Genetics of Kidneys in Diabetes (GoKinD) study and identified a genome-wide significant gene demonstrating cross-phenotype effects that was not identified using standard univariate approaches.