Cited by 441Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenetic and phenotypic traits in livestock

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Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses

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Wallace, Chris·2020·PLOS Genetics

DOI 10.1371/journal.pgen.1008720PMC PMC7192519

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Abstract

Horizontal integration of summary statistics from different GWAS traits can be used to evaluate evidence for their shared genetic causality. One popular method to do this is a Bayesian method, coloc, which is attractive in requiring only GWAS summary statistics and no linkage disequilibrium estimates and is now being used routinely to perform thousands of comparisons between traits. Here we show that while most users do not adjust default software values, misspecification of prior parameters can substantially alter posterior inference. We suggest data driven methods to derive sensible prior values, and demonstrate how sensitivity analysis can be used to assess robustness of posterior inference. The flexibility of coloc comes at the expense of an unrealistic assumption of a single causal variant per trait. This assumption can be relaxed by stepwise conditioning, but this requires external software and an LD matrix aligned to study alleles. We have now implemented conditioning within coloc, and propose a new alternative method, masking, that does not require LD and approximates conditioning when causal variants are independent. Importantly, masking can be used in combination with conditioning where allelically aligned LD estimates are available for only a single trait. We have implemented these developments in a new version of coloc which we hope will enable more informed choice of priors and overcome the restriction of the single causal variant assumptions in coloc analysis.

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Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644711
Additional file 6 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
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Additional file 5 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644657
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Additional file 16 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
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Additional file 20 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644702
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Additional file 3 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644651
Additional file 11 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644675
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Additional file 3 of Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
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Additional file 14 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644684
Additional file 10 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644672
Additional file 3 of Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus
Kasela, S., Daniloski, Z., Bollepalli, S., Jordan, T. X., tenOever, B. R., Sanjana, N. E., & Lappalainen, T. (2021) · Figshare · doi:10.6084/m9.figshare.16417541
Additional file 1 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644645
Additional file 2 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644648
Additional file 8 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644666
Additional file 4 of Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
Kasela, S., Ortega, V. E., Martorella, M., Garudadri, S., Nguyen, J., Ampleford, E., Pasanen, A., Nerella, S., Buschur, K. L., Barjaktarevic, I. Z., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14463078
Additional file 7 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644663
Additional file 4 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644654
Additional file 12 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644678
Additional file 17 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644693
Additional file 2 of Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis
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Additional file 15 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644687
Additional file 21 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644708
Additional file 9 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644669
Additional file 2 of Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause
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Additional file 19 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
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Additional file 18 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
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Additional file 13 of TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study
Rajasundaram, S., Zebardast, N., Mehta, P. A., Khawaja, A. P., Warwick, A., Duchinski, K., Burgess, S., Gill, D., Segrè, A. V., & Wiggs, J. L. (2024) · Figshare · doi:10.6084/m9.figshare.26644681
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Authors: Wallace, C.
Affiliations: University of Cambridge (GB)
Corresponding author: Wallace, Chris
ORCID: Wallace, Chris
Venue: PLOS Genetics
Publisher: Public Library of Science (PLoS)
Published: 2020-04-20
Volume: 16
Issue: 4
Pages: e1008720
ISSN: 1553-7390 (ISSN-L)
1553-7404
DOI: 10.1371/journal.pgen.1008720
PMC: PMC7192519
OpenAlex: W3016489931
Cited by: 441
References: 59
Citations by year: 2026: 75 · 2025: 98 · 2024: 123 · 2023: 47 · 2022: 39 · 2021: 43 · 2020: 15
FWCI: 21.26
Type: journal article
Language: en
Update notices: new_version (2020-04-30)
correction (2026-05-19)
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS Genetics (publishedVersion, cc-by)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Apollo (University of Cambridge) (submittedVersion, cc-by)
Apollo (cc-by)
Funders: Wellcome Trust (WT107881)
Medical Research Council (MC UU 00002/4)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords: COLOC, prior specification, prior distributions, sensitivity analysis, masking, linkage disequilibrium, GWAS summary statistics
MeSH terms: Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses

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