CERAMIC: Case-Control Association Testing in Samples with Related Individuals, Based on Retrospective Mixed Model Analysis with Adjustment for Covariates

We consider the problem of genetic association testing of a binary trait in a sample that contains related individuals, where we adjust for relevant covariates and allow for missing data. We propose CERAMIC, an estimating equation approach that can be viewed as a hybrid of logistic regression and linear mixed-effects model (LMM) approaches. CERAMIC extends the recently proposed CARAT method to allow samples with related individuals and to incorporate partially missing data. In simulations, we show that CERAMIC outperforms existing LMM and generalized LMM approaches, maintaining high power and correct type 1 error across a wider range of scenarios. CERAMIC results in a particularly large power increase over existing methods when the sample includes related individuals with some missing data (e.g., when some individuals with phenotype and covariate information have missing genotype), because CERAMIC is able to make use of the relationship information to incorporate partially missing data in the analysis while correcting for dependence. Because CERAMIC is based on a retrospective analysis, it is robust to misspecification of the phenotype model, resulting in better control of type 1 error and higher power than that of prospective methods, such as GMMAT, when the phenotype model is misspecified. CERAMIC is computationally efficient for genomewide analysis in samples of related individuals of almost any configuration, including small families, unrelated individuals and even large, complex pedigrees. We apply CERAMIC to data on type 2 diabetes (T2D) from the Framingham Heart Study. In a genome scan, 9 of the 10 smallest CERAMIC p-values occur in or near either known T2D susceptibility loci or plausible candidates, verifying that CERAMIC is able to home in on the important loci in a genome scan.