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 von 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, Michael J ZillerSchizophrenia Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number5534
JournalNature Communications
Volume15
Issue1
Number of pages28
ISSN2041-1723
DOIs
Publication statusPublished - Jul 2024

Keywords

  • Humans
  • Schizophrenia/genetics
  • Multifactorial Inheritance/genetics
  • Genetic Predisposition to Disease/genetics
  • Coronary Artery Disease/genetics
  • Risk Factors
  • Female
  • Precision Medicine
  • Male
  • Genome-Wide Association Study
  • Middle Aged
  • Polymorphism, Single Nucleotide

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