Journal article
An application of the MR-Horse method to reduce selection bias in genome-wide association studies of disease progression
- Abstract:
- Genome-wide association studies (GWAS) of disease progression are vulnerable to collider bias caused by selection of participants with disease at study entry. This bias introduces spurious associations between disease progression and genetic variants that are truly only associated with disease incidence. Methods of statistical adjustment to reduce this bias have been published, but rely on assumptions regarding the genetic correlation of disease incidence and disease progression which are likely to be violated in many human diseases. MR-Horse is a recently published Bayesian method to estimate the parameters of a general model of genetic pleiotropy in the setting of Mendelian Randomisation. We adapted this method to provide bias-reduced GWAS estimates of associations with disease progression, robust to the genetic correlation of disease incidence and disease progression and robust to the presence of pleiotropic variants with effects on both incidence and progression. We applied this adapted method to simulated GWAS of disease incidence and progression with pleiotropic variants and varying degrees of genetic correlation. When significant genetic correlation was present, the MR-Horse method produced less biased estimates than unadjusted analyses or analyses adjusted using other existing methods. Type 1 error rates with the MR-Horse method were consistently below the nominal 5% level, at the expense of a modest reduction in power. We then applied this method to summary statistics from the CKDGen consortium GWAS of kidney function decline. MR-Horse attenuated the effects of variants with known likely biased effects in the CKDGen GWAS, whilst preserving effects at loci with likely true effects.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.1MB, Terms of use)
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- Publisher copy:
- 10.1038/s41431-025-01845-6
Authors
+ Kidney Research UK
More from this funder
- Funder identifier:
- https://ror.org/02kx7se86
- Grant:
- TF_001_20220706
- TF_001_20220708
- Publisher:
- Springer Nature
- Journal:
- European Journal of Human Genetics More from this journal
- Publication date:
- 2025-06-03
- Acceptance date:
- 2025-03-26
- DOI:
- EISSN:
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1476-5438
- ISSN:
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1018-4813
- Language:
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English
- Keywords:
- Pubs id:
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2099125
- Local pid:
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pubs:2099125
- Deposit date:
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2025-03-26
Terms of use
- Copyright holder:
- Donovan et al.
- Copyright date:
- 2025
- Rights statement:
- Copyright © 2025, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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