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Using imputed genotype data in the joint score tests for genetic association and gene-environment interactions in case-control studies

TitleUsing imputed genotype data in the joint score tests for genetic association and gene-environment interactions in case-control studies
Publication TypeJournal Article
Year of Publication2018
AuthorsSong, M, Wheeler, W, Caporaso, NE, Landi, MT, Chatterjee, N
JournalGenet Epidemiol
Volume42
Pagination146-155
Date PublishedMar
ISBN Number0741-0395
Accession Number29178451
Keywords*empirical-Bayes, *gene-environment independence, *Gene-Environment Interaction, *Genotype, *meta-analysis, *one-step maximum likelihood estimate, *prospective likelihood, *retrospective likelihood, Algorithms, Alleles, Case-Control Studies, Genome-Wide Association Study/*methods, Humans, Likelihood Functions, Logistic Models, Lung Neoplasms/genetics, Models, Genetic, Polymorphism, Single Nucleotide/genetics, Retrospective Studies, Software
Abstract

Genome-wide association studies (GWAS) are now routinely imputed for untyped single nucleotide polymorphisms (SNPs) based on various powerful statistical algorithms for imputation trained on reference datasets. The use of predicted allele counts for imputed SNPs as the dosage variable is known to produce valid score test for genetic association. In this paper, we investigate how to best handle imputed SNPs in various modern complex tests for genetic associations incorporating gene-environment interactions. We focus on case-control association studies where inference for an underlying logistic regression model can be performed using alternative methods that rely on varying degree on an assumption of gene-environment independence in the underlying population. As increasingly large-scale GWAS are being performed through consortia effort where it is preferable to share only summary-level information across studies, we also describe simple mechanisms for implementing score tests based on standard meta-analysis of "one-step" maximum-likelihood estimates across studies. Applications of the methods in simulation studies and a dataset from GWAS of lung cancer illustrate ability of the proposed methods to maintain type-I error rates for the underlying testing procedures. For analysis of imputed SNPs, similar to typed SNPs, the retrospective methods can lead to considerable efficiency gain for modeling of gene-environment interactions under the assumption of gene-environment independence. Methods are made available for public use through CGEN R software package.

PMCID

PMC5811375