Dissecting the genetic overlap between three complex phenotypes with trivariate MiXeR.

Comorbidities are an increasing global health challenge. Accumulating evidence suggests overlapping genetic architectures underlying comorbid complex human traits and disorders. The bivariate causal mixture model (MiXeR) can quantify the polygenic overlap between complex phenotypes beyond global genetic correlation. Still, the pattern of genetic overlap between three distinct phenotypes, which is important to better characterize multimorbidities, has previously not been possible to quantify. Here, we present and validate the trivariate MiXeR tool, which disentangles the pattern of genetic overlap between three phenotypes using summary statistics from genome-wide association studies (GWAS). Our simulations show that the trivariate MiXeR can reliably reconstruct different patterns of genetic overlap. We further demonstrate how the tool can be used to estimate the proportions of genetic overlap between three phenotypes using real GWAS data, providing examples of complex patterns of genetic overlap between diverse human traits and diseases that could not be deduced from bivariate analyses. This contributes to a better understanding of the etiology of complex phenotypes and the nature of their relationship, which may aid in dissecting comorbidity patterns and their biological underpinnings.
Competing Interests: Conflict of Interest Srdjan Djurovic has received speaker’s Honoria from Lundbeck. Anders M. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and the Mohn Medical Imaging and Visualization Centre in Bergen, Norway. He receives funding through a research agreement with General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. Ole A. Andreassen has received speaker fees from Lundbeck, Janssen, Otsuka, and Sunovion and is a consultant to Cortechs.ai and Precision Health AS.