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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

Open Access Proceedings

Methods for adjusting population structure and familial relatedness in association test for collective effect of multiple rare variants on quantitative traits

Qunyuan Zhang*, Doyoung Chung, Aldi Kraja, Ingrid I Borecki and Michael A Province

Author Affiliations

Division of Statistical Genomics, Washington University School of Medicine, 4444 Forest Park Boulevard, St. Louis, MO 63108, USA

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BMC Proceedings 2011, 5(Suppl 9):S35  doi:10.1186/1753-6561-5-S9-S35

Published: 29 November 2011

Abstract

Because of the low frequency of rare genetic variants in observed data, the statistical power of detecting their associations with target traits is usually low. The collapsing test of collective effect of multiple rare variants is an important and useful strategy to increase the power; in addition, family data may be enriched with causal rare variants and therefore provide extra power. However, when family data are used, both population structure and familial relatedness need to be adjusted for the possible inflation of false positives. Using a unified mixed linear model and family data, we compared six methods to detect the association between multiple rare variants and quantitative traits. Through the analysis of 200 replications of the quantitative trait Q2 from the Genetic Analysis Workshop 17 data set simulated for 697 subjects from 8 extended families, and based on quantile-quantile plots under the null and receiver operating characteristic curves, we compared the false-positive rate and power of these methods. We observed that adjusting for pedigree-based kinship gives the best control for false-positive rate, whereas adjusting for marker-based identity by state slightly outperforms in terms of power. An adjustment based on a principal components analysis slightly improves the false-positive rate and power. Taking into account type-1 error, power, and computational efficiency, we find that adjusting for pedigree-based kinship seems to be a good choice for the collective test of association between multiple rare variants and quantitative traits using family data.