Distinct genetic liability profiles define clinically relevant patient strata across common diseases
Authors: Trastulla Lucia , Dolgalev Georgii , Moser Sylvain , Jiménez-Barrón Laura T. , Andlauer Till F. M. , von Scheidt Moritz ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ruderfer Douglas M. , Ripke Stephan , McQuillin Andrew , Stahl Eli A. , Domenici Enrico , Adolfsson Rolf , Agartz Ingrid , Agerbo Esben , Albus Margot , Alexander Madeline , Amin Farooq , Bacanu Silviu A. , Begemann Martin , Belliveau Richard A. , Bene Judit , Bergen Sarah E. , Bevilacqua Elizabeth , Bigdeli Tim B. , Black Donald W. , Blackwood Douglas H. R. , Borglum Anders D. , Bramon Elvira , Bruggeman Richard , Buccola Nancy G. , Buckner Randy L. , Bulik-Sullivan Brendan , Buxbaum Joseph D. , Byerley William , Cahn Wiepke , Cai Guiqing , Campion Dominique , Cantor Rita M. , Carr Vaughan J. , Carrera Noa , Catts Stanley V. , Chambert Kimberley D. , Chan Raymond C. K. , Chen Eric Y. H. , Chen Ronald Y. L. , Cheng Wei , Cheung Eric F. C. , Chong Siow Ann , Cichon Sven , Cloninger C. Robert , Cohen David , Cohen Nadine , Collier David A. , Cormican Paul , Craddock Nicholas , Crowley James J. , Daly Mark J. , Darvasi Ariel , Davidson Michael , Davis Kenneth L. , Degenhardt Franziska , Del Favero Jurgen , Demontis Ditte , Dikeos Dimitris , Dinan Timothy , Djurovic Srdjan , Donohoe Gary , Drapeau Elodie , Duan Jubao , Dudbridge Frank , Ehrenreich Hannelore , Eichhammer Peter , Eriksson Johan , Escott-Price Valentina , Esko Tonu , Essioux Laurent , Farh Kai-How , Farrell Martilias S. , Frank Josef , Franke Lude , Freedman Robert , Freimer Nelson B. , Friedman Joseph I. , Fromer Menachem , Gejman Pablo V. , Genovese Giulio , Georgieva Lyudmila , Giegling Ina , Gill Michael , Giusti-Rodriguez Paola , Godard Stephanie , Goldstein Jacqueline I. , Gopal Srihari , Gratten Jacob , Gurling Hugh , de Haan Lieuwe , Hammer Christian , Hamshere Marian L. , Hansen Mark , Hansen Thomas , Haroutunian Vahram , Hartmann Annette M. , Henskens Frans A. , Herms Stefan , Hirschhorn Joel N. , Hoffmann Per , Hofman Andrea , Hollegaard Mads V. , Hougaard David M. , Huang Hailiang , Hultman Christina M. , Ikeda Masashi , Iwata Nakao , Jablensky Assen V. , Joa Inge , Jonsson Erik G. , Julia Antonio , Kahler Anna K. , Kahn René S. , Kalaydjieva Luba , Karachanak-Yankova Sena , Karjalainen Juha , Kavanagh David , Keller Matthew C. , Kennedy James L. , Khrunin Andrey , Kim Yunjung , Kirov George , Klovins Janis , Knight Jo , Knowles James A. , Konte Bettina , Kucinskas Vaidutis , Kucinskiene Zita Ausrele , Kuzelova-Ptackova Hana , Laurent Claudine , Leboyer Marion , Lee Phil H. , Keong Jimmy Lee Chee , Legge Sophie E. , Lencz Todd , Lerer Bernard , Levinson Douglas F. , Li Miaoxin , Li Qingqin S. , Li Tao , Liang Kung-Yee , Lieberman Jeffrey , Limborska Svetlana , Liu Jianjun , Lonnqvist Jouko , Loughland Carmel M. , Jan Lubinski  , Macek Milan , Magnusson Patrik K. E. , Maher Brion S. , Maier Wolfgang , Malhotra Anil K. , Mallet Jacques , Marsal Sara , Mattheisen Manuel , Mattingsdal Morten , McCarley Robert W. , McCarroll Steven A. , McDonald Colm , McIntosh Andrew M. , Meier Sandra , Meijer Carin J. , Melegh Bela , Melle Ingrid , Mesholam-Gately Raquelle I. , Metspalu Andres , Michie Patricia T. , Milani Lili , Milanova Vihra , Mokrab Younes , Moran Jennifer L. , Morris Derek W. , Mors Ole , Mortensen Preben B. , Mowry Bryan J. , Murphy Kieran C. , Murray Robin M. , Myin-Germeys Inez , Neale Benjamin M. , Nelis Mari , Nenadic Igor , Nertney Deborah A. , Nestadt Gerald , Nicodemus Kristin K. , Nikitina-Zake Liene , Nisenbaum Laura , Nordin Annelie , Nothen Markus M. , O’Callaghan Eadbhard , O’Dushlaine Colm , O’Neill F. Anthony , Oh Sang-Yun , Olincy Ann , Olsen Line , Van Os Jim , Owen Michael J. , Palotie Aarno , Pantelis Christos , Papadimitriou George N. , Parkhomenko Elena , Pato Carlos , Pato Michele T. , Paunio Tiina , Perkins Diana O. , Pers Tune H. , Petryshen Tracey L. , Pietilainen Olli , Pimm Jonathan , Pocklington Andrew J. , Posthuma Danielle , Powell John , Price Alkes , Pulver Ann E. , Purcell Shaun M. , Quested Digby , Rasmussen Henrik B. , Reichenberg Abraham , Reimers Mark A. , Richards Alexander L. , Riley Brien P. , Roffman Joshua L. , Roussos Panos , Dan Rujescu  , Salomaa Veikko , Sanders Alan R. , Schall Ulrich , Schwab Sibylle G. , Scolnick Edward M. , Scott Rodney J. , Seidman Larry J. , Sham Pak C. , Shi Jianxin , Sigurdsson Engilbert , Silverman Jeremy M. , Sim Kang , Slominsky Petr , Smoller Jordan W. , So Hon-Cheong , Soderman Erik , Spencer Chris C. A. , Clair David St , Stefansson Hreinn , Stefansson Kari , Steinberg Stacy , Stogmann Elisabeth , Straub Richard E. , Strengman Eric , Strohmaier Jana , Stroup T. Scott , Subramaniam Mythily , Suvisaari Jaana , Svrakic Dragan M. , Szatkiewicz Jin P. , Thirumalai Srinivas , Toncheva Draga , Tosato Sarah , Treutlein Jens , Visscher Peter M. , Waddington John , Walsh Dermot , Walters James T. R. , Wang Dai , Wang Qiang , Webb Bradley T. , Weinberger Daniel R. , Weiser Mark , Werge Thomas , Wildenauer Dieter B. , Williams Nigel M. , Williams Stephanie , Witt Stephanie H. , Wolen Aaron R. , Wong Emily H. M. , Wormley Brandon K. , Xi Simon , Zai Clement C. , Zheng Xuebin , Zimprich Fritz , Corvin Aiden , Fanous Ayman H. , Rietschel Marcella , Holmans Peter A. , Andreassen Ole A. , Lee S. Hong , Sullivan Patrick F. , Ophoff Roel A. , Wray Naomi R. , Sklar Pamela , Kendler Kenneth S. , O’Donovan Michael C. , Budde Monika , Heilbronner Urs , Papiol Sergi , Teumer Alexander , Homuth Georg , Völzke Henry , Dörr Marcus , Falkai Peter , Schulze Thomas G. , Gagneur Julien , Iorio Francesco , Müller-Myhsok Bertram , Schunkert Heribert , Ziller Michael J. 
Published: July 2024

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.