title: Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models.
abstract: In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F-distribution tests based on Pillai-Bartlett trace, Hotelling-Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and optimal sequence kernel association test (SKAT-O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F-distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F-distribution tests provide much more significant results than those of F-tests of univariate analysis and SKAT-O for the three biochemical traits. The approximate F-distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT-O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT-O in the univariate case.
authors: Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Yifan
authors: Y
authors: Wang
authors: Aiyi
authors: A
authors: Liu
authors: James L
authors: JL
authors: Mills
authors: Michael
authors: M
authors: Boehnke
authors: Alexander F
authors: AF
authors: Wilson
authors: Joan E
authors: JE
authors: Bailey-Wilson
authors: Momiao
authors: M
authors: Xiong
authors: Colin O
authors: CO
authors: Wu
authors: Ruzong
authors: R
authors: Fan
mesh_terms: D015331:Cohort Studies; D005819:Genetic Markers / Q000235:genetics*; D058685:Genetic Pleiotropy; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D016014:Linear Models; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci; D012984:Software
chemical_list: D005819:Genetic Markers
keywords: association mapping; common variants; complex traits; functional data analysis; multivariate linear models; pleiotropy analysis; quantitative trait loci; rare variants