Efficient generalized least squares method for mixed population and family-based samples in genome-wide association studies.
Genome-wide association studies (GWAS) that draw samples from multiple studies with a mixture of relationship structures are becoming more common. Analytical methods exist for using mixed-sample data, but few methods have been proposed for the analysis of genotype-by-environment (G×E) interactions. Using GWAS data from a study of sarcoidosis susceptibility genes in related and unrelated African Americans, we explored the current analytic options for genotype association testing in studies using both unrelated and family-based designs. We propose a novel method-generalized least squares (GLX)-to estimate both SNP and G×E interaction effects for categorical environmental covariates and compared this method to generalized estimating equations (GEE), logistic regression, the Cochran-Armitage trend test, and the WQLS and MQLS methods. We used simulation to demonstrate that the GLX method reduces type I error under a variety of pedigree structures. We also demonstrate its superior power to detect SNP effects while offering computational advantages and comparable power to detect G×E interactions versus GEE. Using this method, we found two novel SNPs that demonstrate a significant genome-wide interaction with insecticide exposure-rs10499003 and rs7745248, located in the intronic and 3' UTR regions of the FUT9 gene on chromosome 6q16.1.
Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, United States of America.
Jia
J
Li
James
J
Yang
Albert M
AM
Levin
Courtney G
CG
Montgomery
Indrani
I
Datta
Sheri
S
Trudeau
Indra
I
Adrianto
Paul
P
McKeigue
Michael C
MC
Iannuzzi
Benjamin A
BA
Rybicki
D001741:Black or African American / Q000235:genetics*; D004777:Environment; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D016018:Least-Squares Analysis; D016015:Logistic Models; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012507:Sarcoidosis / Q000235:genetics*
GWAS; G×E; gene-by-environment; generalized least squares; mixed samples; sarcoidosis