Inference and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis
Pik Fang Kho,
Pernilla Lif Holgerson,
Nicholas J. Timpson,
Miguel E. Renteria,
Gabriel Cuellar Partida
Posted 06 Dec 2019
bioRxiv DOI: 10.1101/865956
Posted 06 Dec 2019
Background 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 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. Methods 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 a causal architecture plot. We apply this process to body mass index and lipid traits as exemplars of traits where there is strong prior expectation for causal effects and dental caries and periodontitis as exemplars of traits where there is a need for causal inference. Results The results for lipids and BMI suggest that these traits are best viewed as creating consequences 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. Conclusions The automated process is available as part of the MASSIVE pipeline from 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 way visualizing the overall causal map of the human phenome. Key messages 1. The latent causal variable approach uses summary statistics from genome-wide association studies to estimate a parameter termed genetic causality proportion . 2. Systematic estimation of genetic causality proportion for many pairs of traits provides an alternative method for phenome-wide causal inference with some theoretical and practical advantages compared to phenome-wide Mendelian randomization. 3. Using this approach, we confirm that lipid traits are an upstream risk factor for other traits and diseases, and we identify that dental diseases are predominantly a downstream consequence of other traits rather than a cause of poor systemic health. 4. The method assumes no bidirectional causality and no confounding by environmental correlates of genotypes, so care is needed when these assumptions are not met. 5. We developed an automated and accessible pipeline for estimating phenome-wide causal relationships and generating interactive visual summaries.
- Downloaded 378 times
- Download rankings, all-time:
- Site-wide: 70,034
- In genetics: 3,256
- Year to date:
- Site-wide: 82,193
- Since beginning of last month:
- Site-wide: 57,984
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!