Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

2015

Vilhjalmsson, Bjarni J

Yang, Jian

Hayeck, Tristan

Essioux, Laurent

Fanous, Ayman H

Farrell, Martilias S

Frank, Josef

Franke, Lude

Freedman, Robert

Freimer, Nelson B

Friedl, Marion

Friedman, Joseph I

Fromer, Menachem

Won, Hong-Hee

Genovese, Giulio

Georgieva, Lyudmila

Gershon, Elliot S

Giegling, Ina

Giusti-Rodrguez, Paola

Godard, Stephanie

Goldstein, Jacqueline I

Golimbet, Vera

Gopal, Srihari

Gratten, Jacob

Kathiresan, Sekar

Grove, Jakob

de Haan, Lieuwe

Hammer, Christian

Hamshere, Marian L

Hansen, Mark

Hansen, Thomas

Haroutunian, Vahram

Hartmann, Annette M

Henskens, Frans A

Herms, Stefan

Pato, Michele

Hirschhorn, Joel N

Hoffmann, Per

Hofman, Andrea

Hollegaard, Mads V

Hougaard, David M

Ikeda, Masashi

Joa, Inge

Julia, Antonio

Kahn, Rene S

Kalaydjieva, Luba

Pato, Carlos

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

Tamimi, Rulla

Konte, Bettina

Kucinskas, Vaidutis

Kucinskiene, Zita Ausrele

Kuzelova-Ptackova, Hana

Kahler, Anna K

Laurent, Claudine

Keong, Jimmy Lee Chee

Lee, Sang Hong

Legge, Sophie E

Lerer, Bernard

Stahl, Eli

Li, Miaoxin

Li, Tao

Liang, Kung-Yee

Lieberman, Jeffrey

Limborska, Svetlana

Loughland, Carmel M

Lubinski, Jan

Lnnqvist, Jouko

Macek, Milan

Magnusson, Patrik K E

Zaitlen, Noah

Maher, Brion S

Maier, Wolfgang

Mallet, Jacques

Marsal, Sara

Mattheisen, Manuel

Mattingsdal, Morten

McCarley, Robert W

McDonald, Colm

McIntosh, Andrew M

Meier, Sandra

Pasaniuc, Bogdan

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

Belbin, Gillian

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

Finucane, Hilary K

Kenny, Eimear E

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

Schierup, Mikkel H

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

De Jager, Philip

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

Patsopoulos, Nikolaos 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

McCarroll, Steve

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

Daly, Mark

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

Purcell, Shaun

Subramaniam, Mythily

Suvisaari, Jaana

Svrakic, Dragan M

Szatkiewicz, Jin P

Sderman, Erik

Thirumalai, Srinivas

Toncheva, Draga

Tooney, Paul A

Tosato, Sarah

Veijola, Juha

Chasman, Daniel

Waddington, John

Walsh, Dermot

Wang, Dai

Wang, Qiang

Webb, Bradley T

Weiser, Mark

Wildenauer, Dieter B

Williams, Nigel M

Williams, Stephanie

Witt, Stephanie H

Neale, Benjamin

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

Goddard, Michael

Visscher, Peter M

Adolfsson, Rolf

Andreassen, Ole A

Blackwood, Douglas H R

Bramon, Elvira

Buxbaum, Joseph D

Borglum, Anders D

Cichon, Sven

Darvasi, Ariel

Domenici, Enrico

Gusev, Alexander

Visscher, Peter M

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

Kraft, Peter

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

Patterson, Nick

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

Price, Alkes L

Riley, Brien P

Rujescu, Dan

Sham, Pak C

Sklar, Pamela

St Clair, David

Weinberger, Daniel R

Wendland, Jens R

Werge, Thomas

Daly, Mark J

Sullivan, Patrick F

Ripke, Stephan

O'Donovan, Michael C

Kraft, Peter

Hunter, David J

Adank, Muriel

Ahsan, Habibul

Aittomaki, Kristiina

Baglietto, Laura

Berndt, Sonja

Blomquist, Carl

Canzian, Federico

Neale, Benjamin M

Chang-Claude, Jenny

Chanock, Stephen J

Crisponi, Laura

Czene, Kamila

Dahmen, Norbert

Silva, Isabel dos Santos

Easton, Douglas

Eliassen, A Heather

Figueroa, Jonine

Fletcher, Olivia

Corvin, Aiden

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

Walters, James T R

Irwanto, Astrid

Johansson, Mattias

Kaaks, Rudolf

Kibriya, Muhammad G

Lichtner, Peter

Lindstrom, Sara

Liu, Jianjun

Lund, Eiliv

Makalic, Enes

Meindl, Alfons

Farh, Kai-How

Meijers-Heijboer, Hanne

Muller-Myhsok, Bertram

Muranen, Taru A

Nevanlinna, Heli

Peeters, Petra H

Peto, Julian

Prentice, Ross L

Rahman, Nazneen

Sanchez, Maria Jose

Schmidt, Daniel F

Holmans, Peter A

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

Lindstrom, Sara

Lee, Phil

Yang, Rose

Zheng, Wei

Bulik-Sullivan, Brendan

Collier, David A

Huang, Hailiang

Pers, Tune H

Agartz, Ingrid

Agerbo, Esben

Albus, Margot

Alexander, Madeline

Amin, Farooq

Ripke, Stephan

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

Genovese, Giulio

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

Loh, Po-Ru

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

Bhatia, Gaurav

Craddock, Nick

Crowley, James J

Curtis, David

Davidson, Michael

Davis, Kenneth L

Degenhardt, Franziska

Del Favero, Jurgen

DeLisi, Lynn E

Demontis, Ditte

Dikeos, Dimitris

Do, Ron

Dinan, Timothy

Djurovic, Srdjan

Donohoe, Gary

Drapeau, Elodie

Duan, Jubao

Dudbridge, Frank

Durmishi, Naser

Eichhammer, Peter

Eriksson, Johan

Escott-Price, Valentina

Journal Article

en

Publication

Cell Press

United States of America

10.1016/j.ajhg.2015.09.001

une:22269

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.

link

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

1537-6605

0002-9297

576

592