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Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores
Vilhjálmsson, Bjarni J.;Yang, Jian;Finucane, Hilary K.;Gusev, Alexander;Lindström, Sara;Ripke, Stephan;Genovese, Giulio;Loh, Po Ru;Bhatia, Gaurav;Do, Ron;Hayeck, Tristan;Won, Hong Hee;Ripke, Stephan;Neale, Benjamin M.;Corvin, Aiden;Walters, James T. R.;Farh, Kai How;Holmans, Peter A.;Lee, Phil;Bulik Sullivan, Brendan;Collier, David A.;Huang, Hailiang;Pers, Tune H.;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.;Bruggeman, Richard;Buccola, Nancy G.;Buckner, Randy L.;Byerley, William;Cahn, Wiepke;Cai, Guiqing;Campion, Dominique;Cantor, Rita M.;Carr, Vaughan J.;Carrera, Noa;Catts, Stanley V.;Chambert, Kimberly D.;Chan, Raymond C. K.;Chen, Ronald Y. L.;Chen, Eric Y. H.;Cheng, Wei;Cheung, Eric F. C.;Chong, Siow Ann;Cloninger, C. Robert;Cohen, David;Cohen, Nadine;Cormican, Paul;Craddock, Nick;Crowley, James J.;Curtis, David;Davidson, Michael;Davis, Kenneth L.;Degenhardt, Franziska;Del Favero, Jurgen;Delisi, Lynn E.;Demontis, Ditte;Dikeos, Dimitris;Dinan, Timothy;Djurovic, Srdjan;Donohoe, Gary;Drapeau, Elodie;Duan, Jubao;Dudbridge, Frank;Durmishi, Naser;Eichhammer, Peter;Eriksson, Johan;Escott Price, Valentina;Essioux, Laurent;Fanous, Ayman H.;Farrell, Martilias S.;Frank, Josef;Franke, Lude;Freedman, Robert;Freimer, Nelson B.;Friedl, Marion;Friedman, Joseph I.;Fromer, Menachem;Genovese, Giulio;Georgieva, Lyudmila;Gershon, Elliot S.;Giegling, Ina;Giusti Rodrguez, Paola;Godard, Stephanie;Goldstein, Jacqueline I.;Golimbet, Vera;Gopal, Srihari;Gratten, Jacob;Grove, Jakob;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.;Ikeda, Masashi;Joa, Inge;Julia, Antonio;Kahn, Rene S.;Kalaydjieva, Luba;Karachanak Yankova, Sena;Karjalainen, Juha;Kavanagh, David;Keller, Matthew C.;Kelly, Brian J.;Kennedy, James L.;Khrunin, Andrey;Kim, Yunjung;Klovins, Janis;Knowles, James A.;Konte, Bettina;Kucinskas, Vaidutis;Kucinskiene, Zita Ausrele;Kuzelova Ptackova, Hana;Kahler, Anna K.;Laurent, Claudine;Keong, Jimmy Lee Chee;Lee, S. Hong;Legge, Sophie E.;Lerer, Bernard;Li, Miaoxin;Li, Tao;Liang, Kung Yee;Lieberman, Jeffrey;Limborska, Svetlana;Loughland, Carmel M.;Lubinski, Jan;Lnnqvist, Jouko;Macek, Milan;Magnusson, Patrik K. E.;Maher, Brion S.;Maier, Wolfgang;Mallet, Jacques;Marsal, Sara;Mattheisen, Manuel;Mattingsdal, Morten;Mccarley, Robert W.;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;Morris, Derek W.;Mors, Ole;Mortensen, Preben B.;Murphy, Kieran C.;Murray, Robin M.;Myin Germeys, Inez;Mller Myhsok, Bertram;Nelis, Mari;Nenadic, Igor;Nertney, Deborah A.;Nestadt, Gerald;Nicodemus, Kristin K.;Nikitina Zake, Liene;Nisenbaum, Laura;Nordin, Annelie;O'Callaghan, Eadbhard;O'Dushlaine, Colm;O'Neill, F. Anthony;Oh, Sang Yun;Olincy, Ann;Olsen, Line;Van Os, Jim;Pantelis, Christos;Papadimitriou, George N.;Papiol, Sergi;Parkhomenko, Elena;Pato, Michele T.;Paunio, Tiina;Pejovic Milovancevic, Milica;Perkins, Diana O.;Pietilinen, Olli;Pimm, Jonathan;Pocklington, Andrew J.;Powell, John;Price, Alkes;Pulver, Ann E.;Purcell, Shaun M.;Quested, Digby;Rasmussen, Henrik B.;Reichenberg, Abraham;Reimers, Mark A.;Richards, Alexander L.;Roffman, Joshua L.;Roussos, Panos;Ruderfer, Douglas M.;Salomaa, Veikko;Sanders, Alan R.;Schall, Ulrich;Schubert, Christian R.;Schulze, Thomas G.;Schwab, Sibylle G.;Scolnick, Edward M.;Scott, Rodney J.;Seidman, Larry J.;Shi, Jianxin;Sigurdsson, Engilbert;Silagadze, Teimuraz;Silverman, Jeremy M.;Sim, Kang;Slominsky, Petr;Smoller, Jordan W.;So, Hon Cheong;Spencer, Chris C. A.;Stahl, Eli A.;Stefansson, Hreinn;Steinberg, Stacy;Stogmann, Elisabeth;Straub, Richard E.;Strengman, Eric;Strohmaier, Jana;Stroup, T. Scott;Subramaniam, Mythily;Suvisaari, Jaana;Svrakic, Dragan M.;Szatkiewicz, Jin P.;Sderman, Erik;Thirumalai, Srinivas;Toncheva, Draga;Tooney, Paul A.;Tosato, Sarah;Veijola, Juha;Waddington, John;Walsh, Dermot;Wang, Dai;Wang, Qiang;Webb, Bradley T.;Weiser, Mark;Wildenauer, Dieter B.;Williams, Nigel M.;Williams, Stephanie;Witt, Stephanie H.;Wolen, Aaron R.;Wong, Emily H. M.;Wormley, Brandon K.;Wu, Jing Qin;Xi, Hualin Simon;Zai, Clement C.;Zheng, Xuebin;Zimprich, Fritz;Wray, Naomi R.;Stefansson, Kari;Visscher, Peter M.;Adolfsson, Rolf;Andreassen, Ole A.;Blackwood, Douglas H. R.;Bramon, Elvira;Buxbaum, Joseph D.;Børglum, Anders D.;Cichon, Sven;Darvasi, Ariel;Domenici, Enrico;Ehrenreich, Hannelore;Esko, Tonu;Gejman, Pablo V.;Gill, Michael;Gurling, Hugh;Hultman, Christina M.;Iwata, Nakao;Jablensky, Assen V.;Jonsson, Erik G.;Kendler, Kenneth S.;Kirov, George;Knight, Jo;Lencz, Todd;Levinson, Douglas F.;Li, Qingqin S.;Liu, Jianjun;Malhotra, Anil K.;Mccarroll, Steven A.;Mcquillin, Andrew;Moran, Jennifer L.;Mortensen, Preben B.;Mowry, Bryan J.;Nthen, Markus M.;Ophoff, Roel A.;Owen, Michael J.;Palotie, Aarno;Pato, Carlos N.;Petryshen, Tracey L.;Posthuma, Danielle;Rietschel, Marcella;Riley, Brien P.;Rujescu, Dan;Sham, Pak C.;Sklar, Pamela;David, S.t. Clair;Weinberger, Daniel R.;Wendland, Jens R.;Werge, Thomas;Daly, Mark J.;Sullivan, Patrick F.;O'Donovan, Michael C.;Kraft, Peter;Hunter, David J.;Adank, Muriel;Ahsan, Habibul;Aittomäki, Kristiina;BAGLIETTO, LAURA;Berndt, Sonja;Blomquist, Carl;Canzian, Federico;Chang Claude, Jenny;Chanock, Stephen J.;Crisponi, Laura;Czene, Kamila;Dahmen, Norbert;Dos Santos Silva, Isabel;Easton, Douglas;Eliassen, A. Heather;Figueroa, Jonine;Fletcher, Olivia;Garcia Closas, Montserrat;Gaudet, Mia M.;Gibson, Lorna;Haiman, Christopher A.;Hall, Per;Hazra, Aditi;Hein, Rebecca;Henderson, Brian E.;Hofman, Albert;Hopper, John L.;Irwanto, Astrid;Johansson, Mattias;Kaaks, Rudolf;Kibriya, Muhammad G.;Lichtner, Peter;Lindström, Sara;Liu, Jianjun;Lund, Eiliv;Makalic, Enes;Meindl, Alfons;Meijers Heijboer, Hanne;Müller Myhsok, Bertram;Muranen, Taru A.;Nevanlinna, Heli;Peeters, Petra H.;Peto, Julian;Prentice, Ross L.;Rahman, Nazneen;Sánchez, María José;Schmidt, Daniel F.;Schmutzler, Rita K.;Southey, Melissa C.;Tamimi, Rulla;Travis, Ruth;Turnbull, Clare;Uitterlinden, Andre G.;Van Der Luijt, Rob B.;Waisfisz, Quinten;Wang, Zhaoming;Whittemore, Alice S.;Yang, Rose;Zheng, Wei;Kathiresan, Sekar;Pato, Michele;Pato, Carlos;Tamimi, Rulla;Stahl, Eli;Zaitlen, Noah;Pasaniuc, Bogdan;Belbin, Gillian;Kenny, Eimear E.;Schierup, Mikkel H.;De Jager, Philip;Patsopoulos, Nikolaos A.;Mccarroll, Steve;Daly, Mark;Purcell, Shaun;Chasman, Daniel;Neale, Benjamin;Goddard, Michael;Visscher, Peter M.;Kraft, Peter;Patterson, Nick;Price, Alkes L.
2015-01-01
Abstract
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/818012
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