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

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

Schizophrenia Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

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
Pages (from-to)	1-28
Number of pages	28
Journal	Nature Communications
Volume	15
Early online date	1 Jul 2024
DOIs	https://doi.org/10.1038/s41467-024-49338-2
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

Funders	Funder number
Bernie Devlin
Bavarian State Ministry of Science and the Arts
Young Investigator Grant
Andrew Chess
Takeda Pharmaceuticals U.S.A.
Joseph Buxbaum
National Institute of Mental Health
National Human Genome Research Institute
University of Pennsylvania Alzheimer’s Disease Core Center
IRP NIMH
National Institute of Neurological Disorders and Stroke
National Cancer Institute
National Institute on Drug Abuse
F. Hoffmann-La Roche
British Heart Foundation
Vahram Haroutunian
Università degli Studi di Trento
National Heart, Lung, and Blood Institute
University of Pittsburgh
Icahn School of Medicine at Mount Sinai
German Centre of Cardiovascular Research
Bavarian State Ministry of Health, Care and Prevention
Dr. Lisa Oehler Foundation
National Alliance for Research on Schizophrenia and Depression
University of Pittsburgh NeuroBioBank
Era-Net Neuron
Schahram Akbarian
DigiMed Bayern	DMB-1805–0001
DHM-MSRM	1530/891 02, SFB 1123
GWPI-BIOPSY	01EW 2009, 01EW 2005
Bundesministerium für Bildung und Forschung	01ZX1614K, 01EE1404H, 01ZX1504, DP3DK111898
Bundesministerium für Bildung und Forschung
Deutsches Zentrum für Herz-Kreislaufforschung	81X2600522
Deutsches Zentrum für Herz-Kreislaufforschung
German Federal Ministry of Economics and Energy	01ZX1904A, ZF4590201BA8
Deutsche Forschungsgemeinschaft	SCHU 1603/4-1, FA241/16-1
Deutsche Forschungsgemeinschaft
European Union’s Horizon Europe research and innovation programme	101057454, 01ZX1706
Foundation for Cardiovascular Research	18CVD02
Foundation for Cardiovascular Research
Horizon 2020 Framework Programme	945151
Horizon 2020 Framework Programme
National Institutes of Health	R01MH093725, R01MH085542, P50MH080405, AG02219, U01MH103392, RO1-MH-075916, R37MH057881, R01MH097276, AG05138, MH06692, HHSN271201300031C, P50MH066392, R01MH110921, P50MH084053S1, R01MH109677, R01MH109897, P50M096891
National Institutes of Health

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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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Robert} and David Cohen and Nadine Cohen and Collier, {David A.} and Paul Cormican and Nicholas Craddock and Crowley, {James J.} and Daly, {Mark J.} and Ariel Darvasi and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {Del Favero}, Jurgen and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Hannelore Ehrenreich and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Tonu Esko and Laurent Essioux and Farh, {Kai How} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Friedman, {Joseph I.} and Menachem Fromer and Gejman, {Pablo V.} and Giulio Genovese and Lyudmila Georgieva and Ina Giegling and Michael Gill and Paola Giusti-Rodriguez and Stephanie Godard and Goldstein, {Jacqueline I.} and Srihari Gopal and Jacob Gratten and Hugh Gurling and {de Haan}, Lieuwe and Christian Hammer and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Hollegaard, {Mads V.} and Hougaard, {David M.} and Hailiang Huang and Hultman, {Christina M.} and Masashi Ikeda and Nakao Iwata and Jablensky, {Assen V.} and Inge Joa and Jonsson, {Erik G.} and Antonio Julia and Kahler, {Anna K.} and Kahn, {Ren{\'e} S.} and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kennedy, {James L.} and Andrey Khrunin and Yunjung Kim and George Kirov and Janis Klovins and Jo Knight and Knowles, {James A.} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, {Zita Ausrele} and Hana Kuzelova-Ptackova and Claudine Laurent and Marion Leboyer and Lee, {Phil H.} and Keong, {Jimmy Lee Chee} and Legge, {Sophie E.} and Todd Lencz and Bernard Lerer and Levinson, {Douglas F.} and Miaoxin Li and Li, {Qingqin S.} and Tao Li and Liang, {Kung Yee} and Jeffrey Lieberman and Svetlana Limborska and Jianjun Liu and Jouko Lonnqvist and Loughland, {Carmel M.} and {Jan Lubinski}, Lubinski and Milan Macek and Magnusson, {Patrik K.E.} and Maher, {Brion S.} and Wolfgang Maier and Malhotra, {Anil K.} and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and McCarroll, {Steven A.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Moran, {Jennifer L.} and Morris, {Derek W.} and Ole Mors and Mortensen, {Preben B.} and Mowry, {Bryan J.} and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Neale, {Benjamin M.} and Mari Nelis and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Liene Nikitina-Zake and Laura Nisenbaum and Annelie Nordin and Nothen, {Markus M.} and Eadbhard O{\textquoteright}Callaghan and Colm O{\textquoteright}Dushlaine and O{\textquoteright}Neill, {F. 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note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41467-024-49338-2",

language = "English",

volume = "15",

pages = "1--28",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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TY - JOUR

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 - Ruderfer, Douglas M.

AU - Ripke, Stephan

AU - McQuillin, Andrew

AU - Stahl, Eli A.

AU - Domenici, Enrico

AU - Adolfsson, Rolf

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Blackwood, Douglas H.R.

AU - Borglum, Anders D.

AU - Bramon, Elvira

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Bulik-Sullivan, Brendan

AU - Buxbaum, Joseph D.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Catts, Stanley V.

AU - Chambert, Kimberley D.

AU - Chan, Raymond C.K.

AU - Chen, Eric Y.H.

AU - Chen, Ronald Y.L.

AU - Cheng, Wei

AU - Cheung, Eric F.C.

AU - Chong, Siow Ann

AU - Cichon, Sven

AU - Cloninger, C. Robert

AU - Cohen, David

AU - Cohen, Nadine

AU - Collier, David A.

AU - Cormican, Paul

AU - Craddock, Nicholas

AU - Crowley, James J.

AU - Daly, Mark J.

AU - Darvasi, Ariel

AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - Degenhardt, Franziska

AU - Del Favero, Jurgen

AU - Demontis, Ditte

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Duan, Jubao

AU - Dudbridge, Frank

AU - Ehrenreich, Hannelore

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Escott-Price, Valentina

AU - Esko, Tonu

AU - Essioux, Laurent

AU - Farh, Kai How

AU - Farrell, Martilias S.

AU - Frank, Josef

AU - Franke, Lude

AU - Freedman, Robert

AU - Freimer, Nelson B.

AU - Friedman, Joseph I.

AU - Fromer, Menachem

AU - Gejman, Pablo V.

AU - Genovese, Giulio

AU - Georgieva, Lyudmila

AU - Giegling, Ina

AU - Gill, Michael

AU - Giusti-Rodriguez, Paola

AU - Godard, Stephanie

AU - Goldstein, Jacqueline I.

AU - Gopal, Srihari

AU - Gratten, Jacob

AU - Gurling, Hugh

AU - de Haan, Lieuwe

AU - Hammer, Christian

AU - Hamshere, Marian L.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Haroutunian, Vahram

AU - Hartmann, Annette M.

AU - Henskens, Frans A.

AU - Herms, Stefan

AU - Hirschhorn, Joel N.

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Hollegaard, Mads V.

AU - Hougaard, David M.

AU - Huang, Hailiang

AU - Hultman, Christina M.

AU - Ikeda, Masashi

AU - Iwata, Nakao

AU - Jablensky, Assen V.

AU - Joa, Inge

AU - Jonsson, Erik G.

AU - Julia, Antonio

AU - Kahler, Anna K.

AU - Kahn, René S.

AU - Kalaydjieva, Luba

AU - Karachanak-Yankova, Sena

AU - Karjalainen, Juha

AU - Kavanagh, David

AU - Keller, Matthew C.

AU - Kennedy, James L.

AU - Khrunin, Andrey

AU - Kim, Yunjung

AU - Kirov, George

AU - Klovins, Janis

AU - Knight, Jo

AU - Knowles, James A.

AU - Konte, Bettina

AU - Kucinskas, Vaidutis

AU - Kucinskiene, Zita Ausrele

AU - Kuzelova-Ptackova, Hana

AU - Laurent, Claudine

AU - Leboyer, Marion

AU - Lee, Phil H.

AU - Keong, Jimmy Lee Chee

AU - Legge, Sophie E.

AU - Lencz, Todd

AU - Lerer, Bernard

AU - Levinson, Douglas F.

AU - Li, Miaoxin

AU - Li, Qingqin S.

AU - Li, Tao

AU - Liang, Kung Yee

AU - Lieberman, Jeffrey

AU - Limborska, Svetlana

AU - Liu, Jianjun

AU - Lonnqvist, Jouko

AU - Loughland, Carmel M.

AU - Jan Lubinski, Lubinski

AU - Macek, Milan

AU - Magnusson, Patrik K.E.

AU - Maher, Brion S.

AU - Maier, Wolfgang

AU - Malhotra, Anil K.

AU - Mallet, Jacques

AU - Marsal, Sara

AU - Mattheisen, Manuel

AU - Mattingsdal, Morten

AU - McCarley, Robert W.

AU - McCarroll, Steven A.

AU - McDonald, Colm

AU - McIntosh, Andrew M.

AU - Meier, Sandra

AU - Meijer, Carin J.

AU - Melegh, Bela

AU - Melle, Ingrid

AU - Mesholam-Gately, Raquelle I.

AU - Metspalu, Andres

AU - Michie, Patricia T.

AU - Milani, Lili

AU - Milanova, Vihra

AU - Mokrab, Younes

AU - Moran, Jennifer L.

AU - Morris, Derek W.

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Mowry, Bryan J.

AU - Murphy, Kieran C.

AU - Murray, Robin M.

AU - Myin-Germeys, Inez

AU - Neale, Benjamin M.

AU - Nelis, Mari

AU - Nenadic, Igor

AU - Nertney, Deborah A.

AU - Nestadt, Gerald

AU - Nicodemus, Kristin K.

AU - Nikitina-Zake, Liene

AU - Nisenbaum, Laura

AU - Nordin, Annelie

AU - Nothen, Markus M.

AU - O’Callaghan, Eadbhard

AU - O’Dushlaine, Colm

AU - O’Neill, F. Anthony

AU - Oh, Sang Yun

AU - Olincy, Ann

AU - Olsen, Line

AU - Van Os, Jim

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Pantelis, Christos

AU - Papadimitriou, George N.

AU - Parkhomenko, Elena

AU - Pato, Carlos

AU - Pato, Michele T.

AU - Paunio, Tiina

AU - Perkins, Diana O.

AU - Pers, Tune H.

AU - Petryshen, Tracey L.

AU - Pietilainen, Olli

AU - Pimm, Jonathan

AU - Pocklington, Andrew J.

AU - Posthuma, Danielle

AU - Powell, John

AU - Price, Alkes

AU - Pulver, Ann E.

AU - Purcell, Shaun M.

AU - Quested, Digby

AU - Rasmussen, Henrik B.

AU - Reichenberg, Abraham

AU - Reimers, Mark A.

AU - Richards, Alexander L.

AU - Riley, Brien P.

AU - Roffman, Joshua L.

AU - Roussos, Panos

AU - Dan Rujescu, Rujescu

AU - Salomaa, Veikko

AU - Sanders, Alan R.

AU - Schall, Ulrich

AU - Schwab, Sibylle G.

AU - Scolnick, Edward M.

AU - Scott, Rodney J.

AU - Seidman, Larry J.

AU - Sham, Pak C.

AU - Shi, Jianxin

AU - Sigurdsson, Engilbert

AU - Silverman, Jeremy M.

AU - Sim, Kang

AU - Slominsky, Petr

AU - Smoller, Jordan W.

AU - So, Hon Cheong

AU - Soderman, Erik

AU - Spencer, Chris C.A.

AU - Clair, David St

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Steinberg, Stacy

AU - Stogmann, Elisabeth

AU - Straub, Richard E.

AU - Strengman, Eric

AU - Strohmaier, Jana

AU - Stroup, T. Scott

AU - Subramaniam, Mythily

AU - Suvisaari, Jaana

AU - Svrakic, Dragan M.

AU - Szatkiewicz, Jin P.

AU - Thirumalai, Srinivas

AU - Toncheva, Draga

AU - Tosato, Sarah

AU - Treutlein, Jens

AU - Visscher, Peter M.

AU - Waddington, John

AU - Walsh, Dermot

AU - Walters, James T.R.

AU - Wang, Dai

AU - Wang, Qiang

AU - Webb, Bradley T.

AU - Weinberger, Daniel R.

AU - Weiser, Mark

AU - Werge, Thomas

AU - Wildenauer, Dieter B.

AU - Williams, Nigel M.

AU - Williams, Stephanie

AU - Witt, Stephanie H.

AU - Wolen, Aaron R.

AU - Wong, Emily H.M.

AU - Wormley, Brandon K.

AU - Xi, Simon

AU - Zai, Clement C.

AU - Zheng, Xuebin

AU - Zimprich, Fritz

AU - Corvin, Aiden

AU - Fanous, Ayman H.

AU - Rietschel, Marcella

AU - Holmans, Peter A.

AU - Andreassen, Ole A.

AU - Lee, S. Hong

AU - Sullivan, Patrick F.

AU - Ophoff, Roel A.

AU - Wray, Naomi R.

AU - Sklar, Pamela

AU - Kendler, Kenneth S.

AU - O’Donovan, Michael C.

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

PY - 2024

Y1 - 2024

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.

UR - http://www.scopus.com/inward/record.url?scp=85197716640&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85197716640&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-49338-2

DO - 10.1038/s41467-024-49338-2

M3 - Article

C2 - 38951512

AN - SCOPUS:85197716640

SN - 2041-1723

VL - 15

SP - 1

EP - 28

JO - Nature Communications

JF - Nature Communications

M1 - 5534

ER -

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

Abstract

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