More and more large cohort studies have conducted or are conducting genome-wide association studies (GWAS) to reveal the genetic components of many complex human diseases. These large cohort studies often collected a broad array of correlated phenotypes that reflect common physiological processes. By jointly analyzing these correlated traits, we can gain more power by aggregating multiple weak effects and shed light on the mechanisms underlying complex human diseases. The majority of existing multi-trait association test methods are based on jointly modeling the multivariate traits conditional on the genotype as covariate, and can readily accommodate the imputed SNPs by using their imputed dosage as a covariate. An alternative class of multitrait association tests is based on the inverted regression, which models the distribution of genotypes conditional on the covariate and multivariate traits, and has been shown to have competitive performance. To our knowledge, all existing inverted regression approaches have implicitly used the "best-guess" genotypes, which is not efficient and known to lead to dramatic power loss, and there have not been any proposed methods of incorporating imputation uncertainty into inverted regressions. In this work, we propose a general and efficient framework that can account for the imputation uncertainty to further improve the association test power of inverted regression models for imputed SNPs. We demonstrate through extensive numerical studies that the proposed method has competitive performance. We further illustrate its usefulness by application to association test of diabetes-related glycemic traits in the Atherosclerosis Risk in Communities (ARIC) Study.
Bibliographical noteFunding Information:
This research was supported in part by NIH grant GM083345 and CA134848.We are grateful to the University of Minnesota Supercomputing Institute for assistance with the computations. We want to thank the associate editor and reviewers for their constructive comments which have greatly improved the presentation of the paper. The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.