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

Trastulla, Lucia, Dolgalev, Georgii, Moser, Sylvain, Jiménez-Barrón, Laura, Andlauer, Till, von Scheidt, Moritz, Schizophrenia Working Group of the Psychiatric Genomics Consorti, Budde, Monika, Heilbronner, Urs, Papiol, Sergei, Teumer, Alexander, Homouth, Georg, Falkai, Peter, Volzke, Henry, Dorr, Marcus, Schulze, Thomas, Gagneur, Julien, Iorio, Francesco, Müller-Myhsok, Bertram, Schunkert, Heribert, Ziller, Michael, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, Carrera, Noa ORCID: https://orcid.org/0000-0003-0739-0382, Craddock, Nicholas ORCID: https://orcid.org/0000-0003-2171-0610, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Georgieva, Lyudmila, Hamshere, Marian L. ORCID: https://orcid.org/0000-0002-8990-0958, Kavanagh, David, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Legge, Sophie, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Pocklington, Andrew ORCID: https://orcid.org/0000-0002-2137-0452, Richards, Alexander L., Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Williams, Nigel M. ORCID: https://orcid.org/0000-0003-1177-6931 and Holmans, Peter A. ORCID: https://orcid.org/0000-0003-0870-9412 2024. Distinct genetic liability profiles define clinically relevant patient strata across common diseases. Nature Communications 15 , 5534. 10.1038/s41467-024-49338-2

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	Cardiff University authors contributed as part of the Schizophrenia Working Group of the Psychiatric Genomics Consortium
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	17 April 2024
Date of Acceptance:	11 April 2024
Last Modified:	08 Jul 2024 12:31
URI:	https://orca.cardiff.ac.uk/id/eprint/168027

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