Adaptive-weight burden test for associations between quantitative traits and genotype data with complex correlations

Xiaowei Wu, Ting Guan, Dajiang Liu, Luis G.León Novelo, Dipankar Bandyopadhyay

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

High throughput sequencing has often been used to screen samples from pedigrees or with population structure, producing genotype data with complex correlations caused by both familial relation and linkage disequilibrium. With such data it is critical to account for these genotypic correlations when assessing the contribution of multiple variants by gene or pathway. Recognizing the limitations of existing association testing methods, we propose Adaptive-weight Burden Test (ABT), a retrospective, mixed model test for genetic association of quantitative traits on genotype data with complex correlations. This method makes full use of genotypic correlations across both samples and variants and adopts “data driven” weights to improve power. We derive the ABT statistic and its explicit distribution under the null hypothesis and demonstrate through simulation studies that it is generally more powerful than the fixed-weight burden test and family-based SKAT in various scenarios, controlling for the type I error rate. Further investigation reveals the connection of ABT with kernel tests, as well as the adaptability of its weights to the direction of genetic effects. The application of ABT is illustrated by a gene-based association analysis of fasting glucose using data from the NHLBI “Grand Opportunity” Exome Sequencing Project.

Original languageEnglish (US)
Pages (from-to)1558-1582
Number of pages25
JournalAnnals of Applied Statistics
Volume12
Issue number3
DOIs
StatePublished - Sep 1 2018

Fingerprint

Genotype
Genes
Glucose
Throughput
Statistics
Testing
Sequencing
Gene
Genetic Association
Linkage Disequilibrium
Population Structure
Pedigree
Type I Error Rate
Mixed Model
Burden
Adaptability
Data-driven
Null hypothesis
High Throughput
Test Statistic

All Science Journal Classification (ASJC) codes

  • Statistics and Probability
  • Modeling and Simulation
  • Statistics, Probability and Uncertainty

Cite this

Wu, Xiaowei ; Guan, Ting ; Liu, Dajiang ; Novelo, Luis G.León ; Bandyopadhyay, Dipankar. / Adaptive-weight burden test for associations between quantitative traits and genotype data with complex correlations. In: Annals of Applied Statistics. 2018 ; Vol. 12, No. 3. pp. 1558-1582.
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Adaptive-weight burden test for associations between quantitative traits and genotype data with complex correlations. / Wu, Xiaowei; Guan, Ting; Liu, Dajiang; Novelo, Luis G.León; Bandyopadhyay, Dipankar.

In: Annals of Applied Statistics, Vol. 12, No. 3, 01.09.2018, p. 1558-1582.

Research output: Contribution to journalArticle

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