Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

S., Schizophrenia Working Group of the Psychiatric Genomics Consortium (Ripke; Neale, Bm; Vilhjálmsson, Bjarni J.; Yang, Jian; Finucane, Hilary Kiyo; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Walters, Jt; Do, Ron; Farh, Kh; Hayeck, Tristan; Won, Hong-Hee; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Holmans, Pa; Zaitlen, Noah; Pasaniuc, Bogdan; Collier, Da; Belbin, Gillian; Kenny, Eimear Ee; Pers, Th; Schierup, Mikkel H.; De Jager, Philip; Patsopoulos, Nikolaos A.; Bacanu, Sa; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Belliveau, Ra; Neale, Benjamin; Goddard, Michael; Bergen, Se; Kraft, Peter; Patterson, Nick J.; Price, Alkes L.; Bigdeli, Tb; Corvin, Aiden; Black, Dw; Lee, Phil; Buccola, Ng; Bulik-Sullivan, Brendan; Buckner, Rl; Huang, Hailiang; Cantor, Rm; Agartz, Ingrid; Carr, Vj; Agerbo, Esben; Albus, Margot; Catts, Sv; Alexander, Madeline; Amin, Farooq; Chambert, Kd; Begemann, Martin; Bene, Judit; Chan, Rc; Bevilacqua, Elizabeth; Delisi, Lynn E.; Bruggeman, Richard; Chen, Ry; Byerley, William; Chen, Ey; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cheung, Ef; Carrera, Noa; Chong, Sa; Davis, Kl; Del, Favero J; DeLisi, Le; Fanous, Ah; Cheng, Wei; Freimer, Nb; Friedman, Ji; Cloninger, Cr Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James Jj; Gershon, Es; Curtis, David; Davidson, Michael; Goldstein, Ji; Degenhardt, Franziska; De, Haan L; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Hamshere, Ml; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Hartmann, Am; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Henskens, Fa; Friedl, Marion; Hirschhorn, Jn; Fromer, Menachem; Hollegaard, Mv; Georgieva, Lyudmila; Hougaard, Dm; Giegling, Ina; Giusti-Rodrguez, Paola; Godard, Stephanie; Mcdonald, Colm; Golimbet, Vera; Mcintosh, Andrew M.; Gopal, Srihari Gratten J.; Gratten, Jacob; Grove, Jakob; de Haan, Lieuwe; Hammer, Christian; Kahn, Rs; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Keller, Mc; Bj,; Herms, Stefan; Kennedy, Jl; Hoffmann, Per; Hofman, Andrea; Knowles, Ja; Genomics Consortium, Schizophrenia Working Group of the; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kucinskiene, Za; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Kahler, Ak; Karjalainen, Juha; Kavanagh, David; Kelly, Brian J.; Keong, Jl; Consorti, Schizophrenia Working Group of the Psychiatric Genomics; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Legge, Se; Konte, Bettina; Kucinskas, Vaidutis; Variants in Breast Cancer (DRIVE) study, the Discovery Biology and Risk of; Kuzelova-Ptackova, Hana; Liang, Ky; Laurent, Claudine; Lee, Sh Hong; Loughland, Cm; Lerer, Bernard; Magnusson, Pk; Li, Miaoxin; Li, Tao; Maher, Bs; Lieberman, Jeffrey; Limborska, Svetlana; Lubinski, Jan; Lnnqvist, Jouko; McCarley, Rw; Macek, Milan; McIntosh, Am; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; O'Callaghan, Eadbhard; Mattingsdal, Morten; Meijer, Cj; O'Dushlaine, Colm; Meier, Sandra; O'Neill, Fa Anthony; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Ri; Metspalu, Andres; Michie, Pt; Milani, Lili; Milanova, Vihra; Morris, Dw; Mokrab, Younes; Mors, Ole; Mortensen, Pb; Murphy, Kc; Murray, Rm; Myin-Germeys, Inez; Mller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Da; Nestadt, Gerald; Nicodemus, Kristin Kk; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; Oh, Sy; O’Callaghan, Eadbhard; O’Dushlaine, Colm; O’Neill, F. Anthony; Olincy, Ann; Papadimitriou, Gn; Olsen, Line; Van Os, Jim; Pantelis, Christos; Pato, Mt; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Patsopouos, Nikolaos A.; Pietilinen, Olli; Pimm, Jonathan; Perkins, Do; Powell, John; Pocklington, Aj; J.,; Pulver, Ae; So, Hon-Cheong; Quested, Digby; Reichenberg, Abraham; Purcell, Sm; Reimers, Mark A.; Rasmussen, Hb; Richards, Al; Roussos, Panos; Roffman, Jl; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Mccarroll, Steven A.; Stahl, Ea; Mc Carroll, Steve; Seidman, Larry J.; Mcquillin, Andrew; Shi, Jianxin; Ruderfer, Dm; Sigurdsson, Engilbert; Silagadze, Teimuraz; Sim, Kang; Ar, Sanders; Slominsky, Petr; Schubert, Cr; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Schulze, Tg; Stogmann, Elisabeth; Strengman, Eric; Schwab, Sg; Strohmaier, Jana; Stroup, Ts Scott; Subramaniam, Mythily; Suvisaari, Jaana; Scolnick, Em; Sderman, Erik; David, St. Clair; Thirumalai, Srinivas; Toncheva, Draga; Scott, Rj; Tosato, Sarah; Veijola, Juha; Waddington, John; Lj,; Walsh, Dermot; Wang, Dai; Wang, Qiang; O'Donovan, Michael C.; Weiser, Mark; Silverman, Jm; Williams, Stephanie; Smoller, Jw; Zai, Clement Cc; So, Hc; Zheng, Xuebin; Zimprich, Fritz; Stefansson, Kari; Visscher, Peter M.; Spencer, Cc; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Purce, Shaun; Børglum, Anders D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Dos Santos Silva, Isabel; Ehrenreich, Hannelore; Esko, Tonu; Gejman, Pablo V.; Gill, Michael; Straub, Re; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Svrakic, Dm; Jonsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Szatkiewicz, Jp; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Tooney, Pa; 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; Webb, Bt; Sham, Pak C.; Sklar, Pamela; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Wildenauer, Db; Sullivan, Patrick F.; O’Donovan, Michael C.; Hunter, David J.; Adank, Muriel; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Berndt, Sonja; Williams, Nm; Blomquist, Carl; Canzian, Federico; Chang-Claude, Jenny; Chanock, Stephen J.; Witt, Sh; Crisponi, Laura; Czene, Kamila; Dahmen, Norbert; Silva, Isabel dos Santos; Easton, Douglas; Eliassen, A. Heather; Figueroa, Jonine; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Wolen, Ar; Gibson, Lorna; Haiman, Christopher A.; Hall, Per; Wong, Eh; Hazra, Aditi; Hein, Rebecca; Henderson, Brian E.; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Wormley, Bk; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Wu, Jq; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Xi, Hs; Meijers-Heijboer, Hanne; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Wray, Nr; Rahman, Nazneen; Sánchez, María José; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Visscher, Pm); Travis, Ruth; Turnbull, Clare; Uitterlinden, Andre G.; van der Luijt, Rob B.; Waisfisz, Quinten; Wang, Zhaoming; Discovery Biology and Risk of Inherited Variants, in Breast Cancer (DRIVE) study; Whittemore, Alice S.; Yang, Rose; Price, Al; Zheng, Wei; ,

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Bjarni Vilhjalmsson
S. et al., 2015

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Cell Press, American Journal of Human Genetics, 4(97), p. 576-592, 2015

DOI: 10.1016/j.ajhg.2015.09.001

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@article{S.2015,
  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 R(2) 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.},
  author = {S., Schizophrenia Working Group of the Psychiatric Genomics Consortium (Ripke and Neale, Bm and Vilhjálmsson, Bjarni J. and Yang, Jian and Finucane, Hilary Kiyo and Gusev, Alexander and Lindström, Sara and Ripke, Stephan and Genovese, Giulio and Loh, Po-Ru and Bhatia, Gaurav and Walters, Jt and Do, Ron and Farh, Kh and Hayeck, Tristan and Won, Hong-Hee and Kathiresan, Sekar and Pato, Michele and Pato, Carlos and Tamimi, Rulla and Holmans, Pa and Zaitlen, Noah and Pasaniuc, Bogdan and Collier, Da and Belbin, Gillian and Kenny, Eimear Ee and Pers, Th and Schierup, Mikkel H. and De Jager, Philip and Patsopoulos, Nikolaos A. and Bacanu, Sa and McCarroll, Steve and Daly, Mark and Purcell, Shaun and Chasman, Daniel and Belliveau, Ra and Neale, Benjamin and Goddard, Michael and Bergen, Se and Kraft, Peter and Patterson, Nick J. and Price, Alkes L. and Bigdeli, Tb and Corvin, Aiden and Black, Dw and Lee, Phil and Buccola, Ng and Bulik-Sullivan, Brendan and Buckner, Rl and Huang, Hailiang and Cantor, Rm and Agartz, Ingrid and Carr, Vj and Agerbo, Esben and Albus, Margot and Catts, Sv and Alexander, Madeline and Amin, Farooq and Chambert, Kd and Begemann, Martin and Bene, Judit and Chan, Rc and Bevilacqua, Elizabeth and Delisi, Lynn E. and Bruggeman, Richard and Chen, Ry and Byerley, William and Chen, Ey and Cahn, Wiepke and Cai, Guiqing and Campion, Dominique and Cheung, Ef and Carrera, Noa and Chong, Sa and Davis, Kl and Del, Favero J and DeLisi, Le and Fanous, Ah and Cheng, Wei and Freimer, Nb and Friedman, Ji and Cloninger, Cr Robert and Cohen, David and Cohen, Nadine and Cormican, Paul and Craddock, Nick and Crowley, James Jj and Gershon, Es and Curtis, David and Davidson, Michael and Goldstein, Ji and Degenhardt, Franziska and De, Haan L and Demontis, Ditte and Dikeos, Dimitris and Dinan, Timothy and Djurovic, Srdjan and Hamshere, Ml and Donohoe, Gary and Drapeau, Elodie and Duan, Jubao and Dudbridge, Frank and Durmishi, Naser and Eichhammer, Peter and Hartmann, Am and Eriksson, Johan and Escott-Price, Valentina and Essioux, Laurent and Farrell, Martilias S. and Frank, Josef and Franke, Lude and Freedman, Robert and Henskens, Fa and Friedl, Marion and Hirschhorn, Jn and Fromer, Menachem and Hollegaard, Mv and Georgieva, Lyudmila and Hougaard, Dm and Giegling, Ina and Giusti-Rodrguez, Paola and Godard, Stephanie and Mcdonald, Colm and Golimbet, Vera and Mcintosh, Andrew M. and Gopal, Srihari Gratten J. and Gratten, Jacob and Grove, Jakob and de Haan, Lieuwe and Hammer, Christian and Kahn, Rs and Hansen, Mark and Hansen, Thomas and Haroutunian, Vahram and Keller, Mc and Bj,  and Herms, Stefan and Kennedy, Jl and Hoffmann, Per and Hofman, Andrea and Knowles, Ja and Genomics Consortium, Schizophrenia Working Group of the and Ikeda, Masashi and Joa, Inge and Julia, Antonio and Kucinskiene, Za and Kalaydjieva, Luba and Karachanak-Yankova, Sena and Kahler, Ak and Karjalainen, Juha and Kavanagh, David and Kelly, Brian J. and Keong, Jl and Consorti, Schizophrenia Working Group of the Psychiatric Genomics and Khrunin, Andrey and Kim, Yunjung and Klovins, Janis and Legge, Se and Konte, Bettina and Kucinskas, Vaidutis and Variants in Breast Cancer (DRIVE) study, the Discovery Biology and Risk of and Kuzelova-Ptackova, Hana and Liang, Ky and Laurent, Claudine and Lee, Sh Hong and Loughland, Cm and Lerer, Bernard and Magnusson, Pk and Li, Miaoxin and Li, Tao and Maher, Bs and Lieberman, Jeffrey and Limborska, Svetlana and Lubinski, Jan and Lnnqvist, Jouko and McCarley, Rw and Macek, Milan and McIntosh, Am and Maier, Wolfgang and Mallet, Jacques and Marsal, Sara and Mattheisen, Manuel and O'Callaghan, Eadbhard and Mattingsdal, Morten and Meijer, Cj and O'Dushlaine, Colm and Meier, Sandra and O'Neill, Fa Anthony and Melegh, Bela and Melle, Ingrid and Mesholam-Gately, Ri and Metspalu, Andres and Michie, Pt and Milani, Lili and Milanova, Vihra and Morris, Dw and Mokrab, Younes and Mors, Ole and Mortensen, Pb and Murphy, Kc and Murray, Rm and Myin-Germeys, Inez and Mller-Myhsok, Bertram and Nelis, Mari and Nenadic, Igor and Nertney, Da and Nestadt, Gerald and Nicodemus, Kristin Kk and Nikitina-Zake, Liene and Nisenbaum, Laura and Nordin, Annelie and Oh, Sy and O’Callaghan, Eadbhard and O’Dushlaine, Colm and O’Neill, F. Anthony and Olincy, Ann and Papadimitriou, Gn and Olsen, Line and Van Os, Jim and Pantelis, Christos and Pato, Mt and Papiol, Sergi and Parkhomenko, Elena and Pato, Michele T. and Paunio, Tiina and Pejovic-Milovancevic, Milica and Patsopouos, Nikolaos A. and Pietilinen, Olli and Pimm, Jonathan and Perkins, Do and Powell, John and Pocklington, Aj and J.,  and Pulver, Ae and So, Hon-Cheong and Quested, Digby and Reichenberg, Abraham and Purcell, Sm and Reimers, Mark A. and Rasmussen, Hb and Richards, Al and Roussos, Panos and Roffman, Jl and Salomaa, Veikko and Sanders, Alan R. and Schall, Ulrich and Mccarroll, Steven A. and Stahl, Ea and Mc Carroll, Steve and Seidman, Larry J. and Mcquillin, Andrew and Shi, Jianxin and Ruderfer, Dm and Sigurdsson, Engilbert and Silagadze, Teimuraz and Sim, Kang and Ar, Sanders and Slominsky, Petr and Schubert, Cr and Stahl, Eli A. and Stefansson, Hreinn and Steinberg, Stacy and Schulze, Tg and Stogmann, Elisabeth and Strengman, Eric and Schwab, Sg and Strohmaier, Jana and Stroup, Ts Scott and Subramaniam, Mythily and Suvisaari, Jaana and Scolnick, Em and Sderman, Erik and David, St. Clair and Thirumalai, Srinivas and Toncheva, Draga and Scott, Rj and Tosato, Sarah and Veijola, Juha and Waddington, John and Lj,  and Walsh, Dermot and Wang, Dai and Wang, Qiang and O'Donovan, Michael C. and Weiser, Mark and Silverman, Jm and Williams, Stephanie and Smoller, Jw and Zai, Clement Cc and So, Hc and Zheng, Xuebin and Zimprich, Fritz and Stefansson, Kari and Visscher, Peter M. and Spencer, Cc and Adolfsson, Rolf and Andreassen, Ole A. and Blackwood, Douglas H. R. and Bramon, Elvira and Buxbaum, Joseph D. and Purce, Shaun and Børglum, Anders D. and Cichon, Sven and Darvasi, Ariel and Domenici, Enrico and Dos Santos Silva, Isabel and Ehrenreich, Hannelore and Esko, Tonu and Gejman, Pablo V. and Gill, Michael and Straub, Re and Gurling, Hugh and Hultman, Christina M. and Iwata, Nakao and Jablensky, Assen V. and Svrakic, Dm and Jonsson, Erik G. and Kendler, Kenneth S. and Kirov, George and Knight, Jo and Lencz, Todd and Levinson, Douglas F. and Szatkiewicz, Jp and Li, Qingqin S. and Liu, Jianjun and Malhotra, Anil K. and Moran, Jennifer L. and Mortensen, Preben B. and Mowry, Bryan J. and Tooney, Pa and Nthen, Markus M. and Ophoff, Roel A. and Owen, Michael J. and Palotie, Aarno and Pato, Carlos N. and Petryshen, Tracey L. and Posthuma, Danielle and Rietschel, Marcella and Riley, Brien P. and Rujescu, Dan and Webb, Bt and Sham, Pak C. and Sklar, Pamela and Weinberger, Daniel R. and Wendland, Jens R. and Werge, Thomas and Daly, Mark J. and Wildenauer, Db and Sullivan, Patrick F. and O’Donovan, Michael C. and Hunter, David J. and Adank, Muriel and Ahsan, Habibul and Aittomäki, Kristiina and Baglietto, Laura and Berndt, Sonja and Williams, Nm and Blomquist, Carl and Canzian, Federico and Chang-Claude, Jenny and Chanock, Stephen J. and Witt, Sh and Crisponi, Laura and Czene, Kamila and Dahmen, Norbert and Silva, Isabel dos Santos and Easton, Douglas and Eliassen, A. Heather and Figueroa, Jonine and Fletcher, Olivia and Garcia-Closas, Montserrat and Gaudet, Mia M. and Wolen, Ar and Gibson, Lorna and Haiman, Christopher A. and Hall, Per and Wong, Eh and Hazra, Aditi and Hein, Rebecca and Henderson, Brian E. and Hofman, Albert and Hopper, John L. and Irwanto, Astrid and Wormley, Bk and Johansson, Mattias and Kaaks, Rudolf and Kibriya, Muhammad G. and Lichtner, Peter and Wu, Jq and Lund, Eiliv and Makalic, Enes and Meindl, Alfons and Xi, Hs and Meijers-Heijboer, Hanne and Müller-Myhsok, Bertram and Muranen, Taru A. and Nevanlinna, Heli and Peeters, Petra H. and Peto, Julian and Prentice, Ross L. and Wray, Nr and Rahman, Nazneen and Sánchez, María José and Schmidt, Daniel F. and Schmutzler, Rita K. and Southey, Melissa C. and Visscher, Pm) and Travis, Ruth and Turnbull, Clare and Uitterlinden, Andre G. and van der Luijt, Rob B. and Waisfisz, Quinten and Wang, Zhaoming and Discovery Biology and Risk of Inherited Variants, in Breast Cancer (DRIVE) study and Whittemore, Alice S. and Yang, Rose and Price, Al and Zheng, Wei and , },
  doi = {10.1016/j.ajhg.2015.09.001},
  journal = {American Journal of Human Genetics},
  month = {oct},
  pages = {576-592},
  title = {Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores},
  url = {https://www.researchgate.net/profile/Bjarni_Vilhjalmsson/publication/282436352_Modeling_Linkage_Disequilibrium_Increases_Accuracy_of_Polygenic_Risk_Scores/links/568cea2108ae153299b7fbca.pdf},
  volume = {97},
  year = {2015}
}

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Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Journal article published in 2015 by Schizophrenia Working Group of the Psychiatric Genomics Consortium (Ripke S., Bm Neale, Bjarni J. Vilhjálmsson

, Jian Yang

, Hilary Kiyo Finucane

, Alexander Gusev

, Sara Lindström

, Stephan Ripke, Giulio Genovese

, Po-Ru Loh

, Gaurav Bhatia

, Jt Walters, Ron Do

, Kh Farh, Tristan Hayeck

and other authors. Schizophrenia Working Group of the Psychiatric Genomics Consortium (Ripke S., Bm Neale, Bjarni J. Vilhjálmsson

, Jian Yang

, Hilary Kiyo Finucane

, Alexander Gusev

, Sara Lindström

, Stephan Ripke, Giulio Genovese

, Po-Ru Loh

, Gaurav Bhatia

, Jt Walters, Ron Do

, Kh Farh, Tristan Hayeck

, Hong-Hee Won

, Sekar Kathiresan

, Michele Pato, Carlos Pato

, Rulla Tamimi

, Pa Holmans, Noah Zaitlen

, Bogdan Pasaniuc

, Da Collier, Gillian Belbin, Eimear Ee Kenny, Th Pers, Mikkel H. Schierup

, Philip De Jager

, Nikolaos A. Patsopoulos

, Sa Bacanu, Steve McCarroll

, Mark Daly

, Shaun Purcell

, Daniel Chasman

, Ra Belliveau, Benjamin Neale

, Michael Goddard

, Se Bergen, Peter Kraft

, Nick J. Patterson

, Alkes L. Price

, Tb Bigdeli, Aiden Corvin, Dw Black, Phil Lee, Ng Buccola, Brendan Bulik-Sullivan, Rl Buckner, Hailiang Huang, Rm Cantor, Ingrid Agartz, Vj Carr, Esben Agerbo, Margot Albus, Sv Catts, Madeline Alexander, Farooq Amin, Kd Chambert, Martin Begemann, Judit Bene, Rc Chan, Elizabeth Bevilacqua, Lynn E. Delisi, Richard Bruggeman, Ry Chen, William Byerley, Ey Chen, Wiepke Cahn, Guiqing Cai, Dominique Campion, Ef Cheung, Noa Carrera, Sa Chong, Kl Davis, Favero J Del, Le DeLisi, Ah Fanous, Wei Cheng, Nb Freimer, Ji Friedman, Cr Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James Jj Crowley, Es Gershon, David Curtis, Michael Davidson, Ji Goldstein, Franziska Degenhardt, Haan L De, Ditte Demontis, Dimitris Dikeos, Timothy Dinan

, Srdjan Djurovic, Ml Hamshere, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Am Hartmann, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Fa Henskens, Marion Friedl, Jn Hirschhorn, Menachem Fromer, Mv Hollegaard, Lyudmila Georgieva, Dm Hougaard, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Colm Mcdonald, Vera Golimbet, Andrew M. Mcintosh, Srihari Gratten J. Gopal, Jacob Gratten, Jakob Grove

, Lieuwe de Haan, Christian Hammer, Rs Kahn, Mark Hansen, Thomas Hansen

, Vahram Haroutunian, Mc Keller, Bj, Stefan Herms, Jl Kennedy, Per Hoffmann, Andrea Hofman, Ja Knowles, Schizophrenia Working Group of the Genomics Consortium

, Masashi Ikeda, Inge Joa, Antonio Julia, Za Kucinskiene, Luba Kalaydjieva, Sena Karachanak-Yankova, Ak Kahler, Juha Karjalainen, David Kavanagh, Brian J. Kelly, Jl Keong, Schizophrenia Working Group of the Psychiatric Genomics Consorti, Andrey Khrunin, Yunjung Kim, Janis Klovins, Se Legge, Bettina Konte, Vaidutis Kucinskas, the Discovery Biology and Risk of Variants in Breast Cancer (DRIVE) study

, Hana Kuzelova-Ptackova, Ky Liang, Claudine Laurent, Sh Hong Lee, Cm Loughland, Bernard Lerer, Pk Magnusson, Miaoxin Li, Tao Li, Bs Maher, Jeffrey Lieberman, Svetlana Limborska, Jan Lubinski, Jouko Lnnqvist, Rw McCarley, Milan Macek, Am McIntosh, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Eadbhard O'Callaghan, Morten Mattingsdal, Cj Meijer, Colm O'Dushlaine, Sandra Meier, Fa Anthony O'Neill, Bela Melegh, Ingrid Melle, Ri Mesholam-Gately, Andres Metspalu, Pt Michie, Lili Milani, Vihra Milanova, Dw Morris, Younes Mokrab, Ole Mors, Pb Mortensen, Kc Murphy, Rm Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Da Nertney, Gerald Nestadt, Kristin Kk Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Sy Oh, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Ann Olincy, Gn Papadimitriou, Line Olsen, Jim Van Os, Christos Pantelis, Mt Pato, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Nikolaos A. Patsopouos, Olli Pietilinen, Jonathan Pimm, Do Perkins, John Powell, Aj Pocklington, J., Ae Pulver, Hon-Cheong So, Digby Quested, Abraham Reichenberg, Sm Purcell, Mark A. Reimers, Hb Rasmussen, Al Richards, Panos Roussos, Jl Roffman, Veikko Salomaa, Alan R. Sanders, Ulrich Schall

, Steven A. Mccarroll, Ea Stahl

, Steve Mc Carroll, Larry J. Seidman, Andrew Mcquillin, Jianxin Shi, Dm Ruderfer

, Engilbert Sigurdsson, Teimuraz Silagadze, Kang Sim, Sanders Ar, Petr Slominsky, Cr Schubert, Eli A. Stahl

, Hreinn Stefansson, Stacy Steinberg, Tg Schulze, Elisabeth Stogmann, Eric Strengman, Sg Schwab, Jana Strohmaier, Ts Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Em Scolnick, Erik Sderman, St. Clair David, Srinivas Thirumalai, Draga Toncheva, Rj Scott, Sarah Tosato, Juha Veijola, John Waddington, Lj, Dermot Walsh, Dai Wang, Qiang Wang, Michael C. O'Donovan, Mark Weiser, Jm Silverman, Stephanie Williams, Jw Smoller, Clement Cc Zai, Hc So, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Peter M. Visscher

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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 R(2) 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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Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

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