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

作者：Lucia Trastulla, Georgii Dolgalev, Sylvain Moser, Laura T. Jiménez-Barrón, Till F. M. Andlauer, Moritz von Scheidt, Douglas M. Ruderfer, Stephan Ripke, Andrew McQuillin, Eli A. Stahl, Enrico Domenici, Rolf Adolfsson, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu‐Alin Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Douglas Blackwood, Anders D. Børglum, Elvira Bramon, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, Brendan Bulik‐Sullivan, Joseph D. Buxbaum, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C. K. Chan, Eric Chen, Ronald Y.L. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, Sven Cichon, C. Robert Cloninger, David Cohen, Nadine Cohen, David Collier, Paul Cormican, Nicholas Craddock, James J. Crowley, Mark J. Daly, Ariel Darvasi, Michael H. Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del‐Favero, Ditte Demontis, Dimitris Dikeos, Timothy G. Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Hannelore Ehrenreich, Peter Eichhammer, Johan G. Eriksson, Valentina Escott‐Price, Tõnu Esko, Laurent Essioux, Kai-How Farh, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Joseph I. Friedman, Menachem Fromer, Pablo V. Gejman, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Michael Gill, Paola Giusti‐Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Srihari Gopal, Jacob Gratten, Hugh Gurling, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Folkmann Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Hailiang Huang, Christina M. Hultman, Masashi Ikeda, Nakao Iwata, Assen Jablensky, Inge Joa, Erik G. Jönsson, Antonio Julià, Anna K. Kähler, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, George Kirov, Jānis Kloviņš, Jo Knight, James A. Knowles, Bettina Konte, Vaidutis Kučinskas, Zita Aušrelė Kučinskienė, Hana Kuzelova-Ptackova, Claudine Laurent, Marion Leboyer, Phil H. Lee, Jimmy Lee, Sophie E. Legge, Todd Lencz, Bernard Lerer, Douglas F. Levinson, Miaoxin Li, Qingqin S. Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Jianjun Liu, Jouko Lönnqvist, Carmel M. Loughland, Jan Lubiński, Milan Maçek, Patrik K. E. Magnusson, Brion S. Maher, Wolfgang Maier, Anil K. Malhotra, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Steven A. McCarroll, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Béla Melegh, Ingrid Melle, Raquelle I. Mesholam‐Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Jennifer L. Moran, Derek W. Morris, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Kieran C. Murphy, Robin Murray, Inez Myin‐Germeys, Benjamin M. Neale, Mari Nelis, Igor Nenadić, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Ņikitina-Zaķe, Laura Nisenbaum, Annelie Nordin, Markus M. Nöthen, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim van Os, Michael J. Owen, Aarno Palotie, Christos Pantelis, George N. Papadimitriou, Elena Parkhomenko, Carlos N. Pato, Michele T. Pato, Tiina Paunio, Diana O. Perkins, Tune H. Pers, Tracey L. Petryshen, Olli Pietiläinen, Jonathan Pimm, Andrew Pocklington, Daniëlle Posthuma, John Powell, Alkes L. Price, Ann E. Pulver, Shaun Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander Richards, Brien P. Riley, Joshua L. Roffman, Panos Roussos, Dan Rujescu, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Pak C. Sham, Jianxin Shi, Engilbert Sigurðsson, Jeremy M. Silverman, Kang Sim, P. A. Slominsky, Jordan W. Smoller, Hon‐Cheong So, Erik Söderman, Chris C. A. Spencer, David St Clair, Hreinn Stefánsson, Kari Stefansson, Stacy Steinberg, Elisabeth Stögmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Švrakić, Jin Szatkiewicz, Srinivas Thirumalai, Драга Тончева, Sarah Tosato, Jens Treutlein, Peter M. Visscher, John L. Waddington, Dermot Walsh, James Walters, Dai Wang, Qiang Wang, Bradley T. Webb, Daniel R. Weinberger, Mark Weiser, Thomas Werge, Dieter B. Wildenauer, Nigel Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily Wong, Brandon Wormley, Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Aiden Corvin, Ayman H. Fanous, Marcella Rietschel, Peter Holmans, Ole A. Andreassen, Sang Lee, Patrick F. Sullivan, Roel A. Ophoff, Naomi R. Wray, Pamela Sklar, Kenneth S. Kendler, Michael O‘Donovan, 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 · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-49338-2 · 被引用次数：10 · 研究领域：Health Systems, Economic Evaluations, Quality of Life、Genomics and Rare Diseases、BRCA gene mutations in cancer

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 medi...