title: Meta-analysis of quantitative pleiotropic traits for next-generation sequencing with multivariate functional linear models.
abstract: To analyze next-generation sequencing data, multivariate functional linear models are developed for a meta-analysis of multiple studies to connect genetic variant data to multiple quantitative traits adjusting for covariates. The goal is to take the advantage of both meta-analysis and pleiotropic analysis in order to improve power and to carry out a unified association analysis of multiple studies and multiple traits of complex disorders. Three types of approximate F -distributions 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. Simulation analysis is performed to evaluate false-positive rates and power of the proposed tests. The proposed methods are applied to analyze lipid traits in eight European cohorts. It is shown that it is more advantageous to perform multivariate analysis than univariate analysis in general, and it is more advantageous to perform meta-analysis of multiple studies instead of analyzing the individual studies separately. The proposed models require individual observations. The value of the current paper can be seen at least for two reasons: (a) the proposed methods can be applied to studies that have individual genotype data; (b) the proposed methods can be used as a criterion for future work that uses summary statistics to build test statistics to meta-analyze the data.
authors.affiliation: 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, MD USA.
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: Laboratory of Epidemiology and Biometry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeesun
authors.initials: J
authors.lastname: Jung
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.affiliation: Data Paradise Inc, Belle Mead, NJ, USA.
authors.forename: Haobo
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Biostatistics, The University of Michigan, Ann Arbor, MI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: 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, MD USA.
authors.forename: Aiyi
authors.initials: A
authors.lastname: Liu
authors.affiliation: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: Department of Epidemiology and Biostatistics, University of Maryland College Park, College Park, MD, USA.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Ting Lee
authors.affiliation: Human Genetics Center, University of Texas-Houston, Houston, TX, USA.
authors.forename: Momiao
authors.initials: M
authors.lastname: Xiong
authors.affiliation: 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, MD USA.
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
mesh_terms: D005189:False Positive Reactions; D058685:Genetic Pleiotropy; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D016014:Linear Models; D008957:Models, Genetic; D015999:Multivariate Analysis; D019655:Quantitative Trait, Heritable; D017422:Sequence Analysis, DNA / Q000379:methods*