Assessment and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis
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Abstract
Hypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power, sample overlap or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments across human phenome. We developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed causal architecture plot. We apply this pipeline to body mass index (BMI) and lipid traits as exemplars of traits where there is strong prior expectation for causal effects, and to dental caries and periodontitis as exemplars of traits where there is a need for causal inference. The results for lipids and BMI suggest that these traits are best viewed as contributing factors on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health. The automated pipeline is implemented in the Complex-Traits Genetics Virtual Lab ( https://vl.genoma.io ) and results are available in https://view.genoma.io . We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a new way visualizing the overall causal map of the human phenome.
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- Authors
- Haworth, S., Kho, P. F., Holgerson, P. L., Hwang, L.-D., Timpson, N. J., Rentería, M. E., Johansson, I., & Cuellar-Partida, G.
- Affiliations
- University of Bristol (GB)
- QIMR Berghofer Medical Research Institute (AU)
- Umeå University (SE)
- The University of Queensland (AU)
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2020-10-03
- Volume
- 29
- Issue
- 2
- Pages
- 300-308
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC7868372
- OpenAlex
- W3090945449
- Cited by
- 29
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 3
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion, other-oa)
- DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Funders
- Department of Education and Training | Australian Research Council (DE180100976)
- Department of Health | National Health and Medical Research Council (GNT1102821)
- 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 › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- dental caries, periodontitis, body mass index, lipid traits, horizontal pleiotropy
- MeSH terms
- Dental Caries, Humans, Periodontitis, Phenotype, Risk Factors, Body Mass Index, Genetic Predisposition to Disease, Multifactorial Inheritance, Genome-Wide Association Study, Mendelian Randomization Analysis
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