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Inference and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis

By Simon Haworth, Pik Fang Kho, Pernilla Lif Holgerson, Liang-Dar Hwang, Nicholas J. Timpson, Miguel E. Renteria, Ingegerd Johansson, Gabriel Cuellar Partida

Posted 06 Dec 2019
bioRxiv DOI: 10.1101/865956

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.

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