Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Lucia Trastulla, Georgii Dolgalev, Sylvain Moser, Laura T. Jiménez-Barrón, Till F. M. Andlauer, Moritz Scheidt, Monika Budde, Urs Heilbronner, Sergi Papiol, Alexander Teumer, Georg Homuth, Henry Völzke, Marcus Dörr, Peter Falkai, Thomas G. Schulze, Julien Gagneur, Francesco Iorio, Bertram Müller-Myhsok, Heribert Schunkert and Michael J. Ziller ()
Additional contact information
Lucia Trastulla: Max Planck Institute of Psychiatry
Georgii Dolgalev: University of Münster
Sylvain Moser: Max Planck Institute of Psychiatry
Laura T. Jiménez-Barrón: Max Planck Institute of Psychiatry
Till F. M. Andlauer: Max Planck Institute of Psychiatry
Moritz Scheidt: Technical University Munich
Monika Budde: LMU Munich
Urs Heilbronner: LMU Munich
Sergi Papiol: Max Planck Institute of Psychiatry
Alexander Teumer: Partner Site Greifswald
Georg Homuth: University Medicine Greifswald
Henry Völzke: Partner Site Greifswald
Marcus Dörr: Partner Site Greifswald
Peter Falkai: Max Planck Institute of Psychiatry
Thomas G. Schulze: LMU Munich
Julien Gagneur: Technical University of Munich
Francesco Iorio: Human Technopole
Bertram Müller-Myhsok: Max Planck Institute of Psychiatry
Heribert Schunkert: Technical University Munich
Michael J. Ziller: Max Planck Institute of Psychiatry

Nature Communications, 2024, vol. 15, issue 1, 1-28

Abstract: Abstract Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

Date: 2024
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DOI: 10.1038/s41467-024-49338-2

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