Adjusting for Heritable Covariates Can Bias Effect Estimates in Genome-Wide Association Studies

In recent years, a number of large-scale genome-wide association studies have been published for human traits adjusted for other correlated traits with a genetic basis. In most studies, the motivation for such an adjustment is to discover genetic variants associated with the primary outcome independ...

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Bibliographic Details
Published in:American journal of human genetics 2015-02, Vol.96 (2), p.329-339
Main Authors: Aschard, Hugues, Vilhjálmsson, Bjarni J., Joshi, Amit D., Price, Alkes L., Kraft, Peter
Format: Article
Language:English
Subjects:
Applications
Bioinformatics
Body Mass Index
Computer Science
Computer Simulation
Correlation analysis
Genetic disorders
Genetic Variation
Genetics
Genome-Wide Association Study
Genome-Wide Association Study - methods
Genomics
Human genetics
Humans
Life Sciences
Meta-analysis
Methodology
Models, Genetic
Quantitative Trait, Heritable
Santé publique et épidémiologie
Simulation
Statistics
Waist Circumference
Waist Circumference - genetics
Waist-Hip Ratio
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Summary:In recent years, a number of large-scale genome-wide association studies have been published for human traits adjusted for other correlated traits with a genetic basis. In most studies, the motivation for such an adjustment is to discover genetic variants associated with the primary outcome independently of the correlated trait. In this report, we contend that this objective is fulfilled when the tested variants have no effect on the covariate or when the correlation between the covariate and the outcome is fully explained by a direct effect of the covariate on the outcome. For all other scenarios, an unintended bias is introduced with respect to the primary outcome as a result of the adjustment, and this bias might lead to false positives. Here, we illustrate this point by providing examples from published genome-wide association studies, including large meta-analysis of waist-to-hip ratio and waist circumference adjusted for body mass index (BMI), where genetic effects might be biased as a result of adjustment for body mass index. Using both theory and simulations, we explore this phenomenon in detail and discuss the ramifications for future genome-wide association studies of correlated traits and diseases.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2014.12.021