The Annals of Applied Statistics

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

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

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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.

Article information

Source
Ann. Appl. Stat., Volume 12, Number 3 (2018), 1558-1582.

Dates
Received: May 2016
Revised: August 2017
First available in Project Euclid: 11 September 2018

Permanent link to this document
https://projecteuclid.org/euclid.aoas/1536652965

Digital Object Identifier
doi:10.1214/17-AOAS1121

Mathematical Reviews number (MathSciNet)
MR3852688

Keywords
Genetic association test burden test kernel test adaptive weight complex genotypic correlation

Citation

Wu, Xiaowei; Guan, Ting; Liu, Dajiang J.; Novelo, Luis G. León; Bandyopadhyay, Dipankar. Adaptive-weight burden test for associations between quantitative traits and genotype data with complex correlations. Ann. Appl. Stat. 12 (2018), no. 3, 1558--1582. doi:10.1214/17-AOAS1121. https://projecteuclid.org/euclid.aoas/1536652965


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Supplemental materials

  • Mathematical justifications and additional results. The supplementary materials of the paper are organized as follows. Supplement S.1 provides the theoretical justification of the covariance matrix of genetic burden score $\boldsymbol{X}$. Supplement S.2 derives the LD covariance of the simulated genotype data for founders. In Supplement S.3, additional results from Section 3.3 on the empirical type-I error of ABT based on $\chi_{m}^{2}$ null distribution in simulation studies are summarized in Table S1. Supplement S.4 includes additional power comparison results at $\alpha=0.01$, for Scenarios II, IV, V, and IX.