Abstract
Currently, the analyses of most genome-wide association studies (GWAS) have been performed on a single phenotype. There is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. Therefore, using only one single phenotype may lose statistical power to identify the underlying genetic mechanism. There is an increasing need to develop and apply powerful statistical tests to detect association between multiple phenotypes and a genetic variant. In this paper, we develop an Adaptive Fisher’s Combination (AFC) method for joint analysis of multiple phenotypes in association studies. The AFC method combines p-values obtained in standard univariate GWAS by using the optimal number of p-values which is determined by the data. We perform extensive simulations to evaluate the performance of the AFC method and compare the power of our method with the powers of TATES, Tippett’s method, Fisher’s combination test, MANOVA, MultiPhen, and SUMSCORE. Our simulation studies show that the proposed method has correct type I error rates and is either the most powerful test or comparable with the most powerful test. Finally, we illustrate our proposed methodology by analyzing whole-genome genotyping data from a lung function study.
Highlights
We evaluate the performance of the proposed method and compare the power of the proposed method with the powers of that uses Extended Simes procedure (TATES), Tippett’s method[27], Fisher’s Combination test (FC)[28], Multivariate Analysis of Variance (MANOVA)[29], joint model of Multiple Phenotypes (MultiPhen)[8], and Sum Score method (SUMSCORE)[12]
genome-wide association studies (GWAS) have identified many variants with each variant affecting multiple phenotypes, which suggests that pleiotropic effects on human complex phenotypes may be widespread
We developed a new method Adaptive Fisher’s Combination (AFC) to jointly analyze multivariate phenotypes in genetic association studies
Summary
Consider a sample of n unrelated individuals. Each individual has K phenotypes. We propose a new method to test the null hypothesis H0: none of the K phenotypes are associated with the genetic variant. We test the association between each phenotypic vector Yk (k = 1, 2, ..., K) and the genotypic score X using a standard GWAS software (e.g. PLINK, Gen/ProbABEL, MaCH, SNPTEST, and FaST-LMM)[30,31,32,33,34,35,36]. Let p1, p2, ...,pK denote the p-values obtained by the standard univariate GWAS. Based on these p-values, we propose an Adaptive. Fisher’s Combination (AFC) method to test the association between multiple phenotypes and the genetic variant.
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