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A data-adaptive sum test for disease association with multiple common or rare variants.

ABSTRACT: Since associations between complex diseases and common variants are typically weak, and approaches to genotyping rare variants (e.g. by next-generation resequencing) multiply, there is an urgent demand to develop powerful association tests that are able to detect disease associations with both common and rare variants. In this article we present such a test. It is based on data-adaptive modifications to a so-called Sum test originally proposed for common variants, which aims to strike a balance between utilizing information on multiple markers in linkage disequilibrium and reducing the cost of large degrees of freedom or of multiple testing adjustment. When applied to multiple common or rare variants in a candidate region, the proposed test is easy to use with 1 degree of freedom and without the need for multiple testing adjustment. We show that the proposed test has high power across a wide range of scenarios with either common or rare variants, or both. In particular, in some situations the proposed test performs better than several commonly used methods.

SUBMITTER: Han F

PROVIDER: S-EPMC2912645 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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A data-adaptive sum test for disease association with multiple common or rare variants.

Han Fang F Pan Wei W

Human heredity 20100423 1

Since associations between complex diseases and common variants are typically weak, and approaches to genotyping rare variants (e.g. by next-generation resequencing) multiply, there is an urgent demand to develop powerful association tests that are able to detect disease associations with both common and rare variants. In this article we present such a test. It is based on data-adaptive modifications to a so-called Sum test originally proposed for common variants, which aims to strike a balance ...[more]

PMID: 20413981

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Project description:Genetic variants associated with disease outcomes can be used to develop personalized treatment. To reach this precision medicine goal, hundreds of large-scale genome-wide association studies (GWAS) have been conducted in the past decade to search for promising genetic variants associated with various traits. They have successfully identified tens of thousands of disease-related variants. However, in total these identified variants explain only part of the variation for most complex traits. There remain many genetic variants with small effect sizes to be discovered, which calls for the development of (a) GWAS with more samples and more comprehensively genotyped variants, for example, the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program is planning to conduct whole genome sequencing on over 100 000 individuals; and (b) novel and more powerful statistical analysis methods. The current dominating GWAS analysis approach is the "single trait" association test, despite the fact that many GWAS are conducted in deeply phenotyped cohorts including many correlated and well-characterized outcomes, which can help improve the power to detect novel variants if properly analyzed, as suggested by increasing evidence that pleiotropy, where a genetic variant affects multiple traits, is the norm in genome-phenome associations. We aim to develop pleiotropy informed powerful association test methods across multiple traits for GWAS. Since it is generally very hard to access individual-level GWAS phenotype and genotype data for those existing GWAS, due to privacy concerns and various logistical considerations, we develop rigorous statistical methods for pleiotropy informed adaptive multitrait association test methods that need only summary association statistics publicly available from most GWAS. We first develop a pleiotropy test, which has powerful performance for truly pleiotropic variants but is sensitive to the pleiotropy assumption. We then develop a pleiotropy informed adaptive test that has robust and powerful performance under various genetic models. We develop accurate and efficient numerical algorithms to compute the analytical P-value for the proposed adaptive test without the need of resampling or permutation. We illustrate the performance of proposed methods through application to joint association test of GWAS meta-analysis summary data for several glycemic traits. Our proposed adaptive test identified several novel loci missed by individual trait based GWAS meta-analysis. All the proposed methods are implemented in a publicly available R package.

Dataset Information

A data-adaptive sum test for disease association with multiple common or rare variants.

Publications

A data-adaptive sum test for disease association with multiple common or rare variants.

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