The DOI matches its Crossref record; 38 of the 40 references it cites were found in a registry or an index.
Adjusting for Heritable Covariates Can Bias Effect Estimates in Genome-Wide Association Studies
Open accessAbstract
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.
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“Disease modifying therapy was not included as it is not a confounder (i.e. does not influence genotype) and may instead introduce collider bias57.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [57]
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“Conditioned GWAS generated from mtCOJO are free of collider biases when estimate causal relationship between depression and each comorbid condition.49”
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In the citing paper
“This adjustment is likely to have biased the effect of genome-wide variants associated with unadjusted WHR (away from the null).”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [17]
Citations
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BackgroundMaternal Pesticide Exposure from Multiple Sources and Selected Congenital Anomalies
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Zhu, Z., Zheng, Z., Zhang, F., Wu, Y., Trzaskowski, M., Maier, R., Robinson, M. R., McGrath, J. J., Visscher, P. M., Wray, N. R., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02317-2 · Cited by 951
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The trans-ancestral genomic architecture of glycemic traits
Chen, J., Spracklen, C. N., Marenne, G., Varshney, A., Corbin, L. J., Luan, J., Willems, S. M., Wu, Y., Zhang, X., Horikoshi, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00852-9 · Cited by 776
Metadata
- Authors
- Aschard, H., Vilhjálmsson, B. J., Joshi, A. D., Price, A. L., & Kraft, P.
- Affiliations
- Harvard University (US)
- Corresponding author
- Aschard, Hugues
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 96
- Issue
- 2
- Pages
- 329-339
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4320269
- OpenAlex
- W1996682563
- Cited by
- 287
- References
- 40
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 30 · 2023: 27 · 2022: 30 · 2021: 33 · 2020: 26 · 2019: 24 · 2018: 26 · 2017: 20 · 2016: 22 · 2015: 8
- FWCI
- 17.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Human Genome Research Institute (R03HG006720)
- National Cancer Institute (U19CA148065)
- National Institute of Environmental Health Sciences (R21ES020754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- genome-wide association study, correlated traits, false positives, waist-to-hip ratio, waist circumference, body mass index, confounding
- MeSH terms
- Computer Simulation, Humans, Models, Genetic, Genetic Variation, Body Mass Index, Quantitative Trait, Heritable, Waist-Hip Ratio, Waist Circumference, Genome-Wide Association Study
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