Using clustering of genetic variants in Mendelian randomization to interrogate the causal pathways underlying multimorbidity from a common risk factor

Mendelian randomization (MR) is an epidemiological approach that utilizes genetic variants as instrumental variables to estimate the causal effect of an exposure on a health outcome. This paper investigates an MR scenario in which genetic variants aggregate into clusters that identify heterogeneous causal effects. Such variant clusters are likely to emerge if they affect the exposure and outcome via distinct biological pathways. In the multi-outcome MR framework, where a shared exposure causally impacts several disease outcomes simultaneously, these variant clusters can provide insights into the common disease-causing mechanisms underpinning the co-occurrence of multiple long-term conditions, a phenomenon known as multimorbidity. To identify such variant clusters, we adapt the general method of agglomerative hierarchical clustering to multi-sample summary-data MR setup, enabling cluster detection based on variant-specific ratio estimates. Particularly, we tailor the method for multi-outcome MR to aid in elucidating the causal pathways through which a common risk factor contributes to multiple morbidities. We show in simulations that our “MR-AHC” method detects clusters with high accuracy, outperforming the existing methods. We apply the method to investigate the causal effects of high body fat percentage on type 2 diabetes and osteoarthritis, uncovering interconnected cellular processes underlying this multimorbid disease pair.