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 Ziller; Schizophrenia Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41467-024-49338-2

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 newspaper › Journal article › Research › peer-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 language	English
Article number	5534
Journal	Nature Communications
Volume	15
Issue	1
Number of pages	28
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-024-49338-2
Publication status	Published - 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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Trastulla, L., Dolgalev, G., Moser, S., Jiménez-Barrón, L. T., Andlauer, T. F. M., von Scheidt, M., Budde, M., Heilbronner, U., Papiol, S., Teumer, A., Homuth, G., Völzke, H., Dörr, M., Falkai, P., Schulze, T. G., Gagneur, J., Iorio, F., Müller-Myhsok, B., Schunkert, H., ... Schizophrenia Working Group of the Psychiatric Genomics Consortium (2024). Distinct genetic liability profiles define clinically relevant patient strata across common diseases. Nature Communications, 15(1), Article 5534. https://doi.org/10.1038/s41467-024-49338-2

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title = "Distinct genetic liability profiles define clinically relevant patient strata across common diseases",

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.",

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author = "Lucia Trastulla and Georgii Dolgalev and Sylvain Moser and Jim{\'e}nez-Barr{\'o}n, {Laura T} and Andlauer, {Till F M} and {von Scheidt}, Moritz and Monika Budde and Urs Heilbronner and Sergi Papiol and Alexander Teumer and Georg Homuth and Henry V{\"o}lzke and Marcus D{\"o}rr and Peter Falkai and Schulze, {Thomas G} and Julien Gagneur and Francesco Iorio and Bertram M{\"u}ller-Myhsok and Heribert Schunkert and Ziller, {Michael J} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and Mortensen, {Preben Bo} and Esben Agerbo",

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Trastulla, L, Dolgalev, G, Moser, S, Jiménez-Barrón, LT, Andlauer, TFM, von Scheidt, M, Budde, M, Heilbronner, U, Papiol, S, Teumer, A, Homuth, G, Völzke, H, Dörr, M, Falkai, P, Schulze, TG, Gagneur, J, Iorio, F, Müller-Myhsok, B, Schunkert, H, Ziller, MJ & Schizophrenia Working Group of the Psychiatric Genomics Consortium 2024, 'Distinct genetic liability profiles define clinically relevant patient strata across common diseases', Nature Communications, vol. 15, no. 1, 5534. https://doi.org/10.1038/s41467-024-49338-2

Distinct genetic liability profiles define clinically relevant patient strata across common diseases. / Trastulla, Lucia; Dolgalev, Georgii; Moser, Sylvain et al.
In: Nature Communications, Vol. 15, No. 1, 5534, 07.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Distinct genetic liability profiles define clinically relevant patient strata across common diseases

AU - Trastulla, Lucia

AU - Dolgalev, Georgii

AU - Moser, Sylvain

AU - Jiménez-Barrón, Laura T

AU - Andlauer, Till F M

AU - von Scheidt, Moritz

AU - Budde, Monika

AU - Heilbronner, Urs

AU - Papiol, Sergi

AU - Teumer, Alexander

AU - Homuth, Georg

AU - Völzke, Henry

AU - Dörr, Marcus

AU - Falkai, Peter

AU - Schulze, Thomas G

AU - Gagneur, Julien

AU - Iorio, Francesco

AU - Müller-Myhsok, Bertram

AU - Schunkert, Heribert

AU - Ziller, Michael J

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Mortensen, Preben Bo

AU - Agerbo, Esben

PY - 2024/7

Y1 - 2024/7

N2 - 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.

AB - 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.

KW - Humans

KW - Schizophrenia/genetics

KW - Multifactorial Inheritance/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Coronary Artery Disease/genetics

KW - Risk Factors

KW - Female

KW - Precision Medicine

KW - Male

KW - Genome-Wide Association Study

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

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U2 - 10.1038/s41467-024-49338-2

DO - 10.1038/s41467-024-49338-2

M3 - Journal article

C2 - 38951512

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5534

ER -

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

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Keywords

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