Distinct genetic liability profiles define clinically relevant patient strata across common diseases
Trastulla L., Dolgalev G., Moser S., Jiménez-Barrón LT., Andlauer TFM., von Scheidt M., Ruderfer DM., Ripke S., McQuillin A., Stahl EA., Domenici E., Adolfsson R., Agartz I., Agerbo E., Albus M., Alexander M., Amin F., Bacanu SA., Begemann M., Belliveau RA., Bene J., Bergen SE., Bevilacqua E., Bigdeli TB., Black DW., Blackwood DHR., Borglum AD., Bramon E., Bruggeman R., Buccola NG., Buckner RL., Bulik-Sullivan B., Buxbaum JD., Byerley W., Cahn W., Cai G., Campion D., Cantor RM., Carr VJ., Carrera N., Catts SV., Chambert KD., Chan RCK., Chen EYH., Chen RYL., Cheng W., Cheung EFC., Chong SA., Cichon S., Cloninger CR., Cohen D., Cohen N., Collier DA., Cormican P., Craddock N., Crowley JJ., Daly MJ., Darvasi A., Davidson M., Davis KL., Degenhardt F., Del Favero J., Demontis D., Dikeos D., Dinan T., Djurovic S., Donohoe G., Drapeau E., Duan J., Dudbridge F., Ehrenreich H., Eichhammer P., Eriksson J., Escott-Price V., Esko T., Essioux L., Farh K-H., Farrell MS., Frank J., Franke L., Freedman R., Freimer NB., Friedman JI., Fromer M., Gejman PV., Genovese G., Georgieva L., Giegling I., Gill M., Giusti-Rodriguez P., Godard S., Goldstein JI., Gopal S., Gratten J., Gurling H., de Haan L., Hammer C., Hamshere ML., Hansen M., Hansen T., Haroutunian V., Hartmann AM., Henskens FA., Herms S., Hirschhorn JN., Hoffmann P., Hofman A., Hollegaard MV., Hougaard DM., Huang H., Hultman CM., Ikeda M., Iwata N., Jablensky AV., Joa I., Jonsson EG., Julia A., Kahler AK., Kahn RS., Kalaydjieva L., Karachanak-Yankova S., Karjalainen J., Kavanagh D., Keller MC., Kennedy JL., Khrunin A., Kim Y., Kirov G., Klovins J., Knight J., Knowles JA., Konte B., Kucinskas V., Kucinskiene ZA., Kuzelova-Ptackova H., Laurent C., Leboyer M., Lee PH., Keong JLC., Legge SE., Lencz T., Lerer B., Levinson DF., Li M., Li QS., Li T., Liang K-Y., Lieberman J., Limborska S., Liu J., Lonnqvist J., Loughland CM., Jan Lubinski None., Macek M., Magnusson PKE., Maher BS., Maier W., Malhotra AK., Mallet J., Marsal S., Mattheisen M., Mattingsdal M., McCarley RW., McCarroll SA., McDonald C., McIntosh AM., Meier S., Meijer CJ., Melegh B., Melle I., Mesholam-Gately RI., Metspalu A., Michie PT., Milani L., Milanova V., Mokrab Y., Moran JL., Morris DW., Mors O., Mortensen PB., Mowry BJ., Murphy KC., Murray RM., Myin-Germeys I., Neale BM., Nelis M., Nenadic I., Nertney DA., Nestadt G., Nicodemus KK., Nikitina-Zake L., Nisenbaum L., Nordin A., Nothen MM., O’Callaghan E., O’Dushlaine C., O’Neill FA., Oh S-Y., Olincy A., Olsen L., Van Os J., Owen MJ., Palotie A., Pantelis C., Papadimitriou GN., Parkhomenko E., Pato C., Pato MT., Paunio T., Perkins DO., Pers TH., Petryshen TL., Pietilainen O., Pimm J., Pocklington AJ., Posthuma D., Powell J., Price A., Pulver AE., Purcell SM., Quested D., Rasmussen HB., Reichenberg A., Reimers MA., Richards AL., Riley BP., Roffman JL., Roussos P., Dan Rujescu None., Salomaa V., Sanders AR., Schall U., Schwab SG., Scolnick EM., Scott RJ., Seidman LJ., Sham PC., Shi J., Sigurdsson E., Silverman JM., Sim K., Slominsky P., Smoller JW., So H-C., Soderman E., Spencer CCA., Clair DS., Stefansson H., Stefansson K., Steinberg S., Stogmann E., Straub RE., Strengman E., Strohmaier J., Stroup TS., Subramaniam M., Suvisaari J., Svrakic DM., Szatkiewicz JP., Thirumalai S., Toncheva D., Tosato S., Treutlein J., Visscher PM., Waddington J., Walsh D., Walters JTR., Wang D., Wang Q., Webb BT., Weinberger DR., Weiser M., Werge T., Wildenauer DB., Williams NM., Williams S., Witt SH., Wolen AR., Wong EHM., Wormley BK., Xi S., Zai CC., Zheng X., Zimprich F., Corvin A., Fanous AH., Rietschel M., Holmans PA., Andreassen OA., Lee SH., Sullivan PF., Ophoff RA., Wray NR., Sklar P., Kendler KS., O’Donovan MC., 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.
AbstractStratified 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.