TY - JOUR
T1 - Distinct genetic liability profiles define clinically relevant patient strata across common diseases
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
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 - Wang, Qiang
AU - Wildenauer, Dieter B.
AU - Williams, Nigel M.
AU - Wong, Emily H.M.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
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
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
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5534
ER -