title: Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models.
abstract: Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs) to account for population structure and relatedness, for both continuous and binary traits. Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait, we show that LMMs are generally inappropriate for analyzing binary traits when population stratification leads to violation of the LMM's constant-residual variance assumption. To overcome this problem, we develop a computationally efficient logistic mixed model approach for genome-wide analysis of binary traits, the generalized linear mixed model association test (GMMAT). This approach fits a logistic mixed model once per GWAS and performs score tests under the null hypothesis of no association between a binary trait and individual genetic variants. We show in simulation studies and real data analysis that GMMAT effectively controls for population structure and relatedness when analyzing binary traits in a wide variety of study designs.
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Chaolong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Conomos
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Stilp
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Mathematics, Tsinghua University, Beijing 100084, P. R. China.
authors.forename: Zilin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Sofer
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Szpiro
authors.affiliation: Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Brehm
authors.affiliation: Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.affiliation: Prevention and Population Sciences Program, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Papanicolaou
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Thornton
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: xlin@hsph.harvard.edu.
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
mesh_terms: D001249:Asthma / Q000235:genetics; D016022:Case-Control Studies; D002489:Central America; D003198:Computer Simulation; D056726:Genetic Association Studies / Q000379:methods*; D005828:Genetics, Population / Q000379:methods*; D060005:Genotyping Techniques; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008957:Models, Genetic; D010641:Phenotype; D058974:Phylogeography; D020641:Polymorphism, Single Nucleotide; D013020:South America