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Am J Hum Genet. 2015 Oct 1;97(4):576-92. doi: 10.1016/j.ajhg.2015.09.001.

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.

Collaborators (368)

Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, Holmans PA, Lee P, Bulik-Sullivan B, Collier DA, Huang H, Pers TH, Agartz I, Agerbo E, Albus M, Alexander M, Amin F, Bacanu SA, Begemann M, Belliveau RA Jr, Bene J, Bergen SE, Bevilacqua E, Bigdeli TB, Black DW, Bruggeman R, Buccola NG, Buckner RL, Byerley W, Cahn W, Cai G, Campion D, Cantor RM, Carr VJ, Carrera N, Catts SV, Chambert KD, Chan RC, Chen RY, Chen EY, Cheng W, Cheung EF, Chong SA, Cloninger CR, Cohen D, Cohen N, Cormican P, Craddock N, Crowley JJ, Curtis D, Davidson M, Davis KL, Degenhardt F, Del Favero J, DeLisi LE, Demontis D, Dikeos D, Dinan T, Djurovic S, Donohoe G, Drapeau E, Duan J, Dudbridge F, Durmishi N, Eichhammer P, Eriksson J, Escott-Price V, Essioux L, Fanous AH, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedl M, Friedman JI, Fromer M, Genovese G, Georgieva L, Gershon ES, Giegling I, Giusti-Rodrguez P, Godard S, Goldstein JI, Golimbet V, Gopal S, Gratten J, Grove J, 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, Ikeda M, Joa I, Julia A, Kahn RS, Kalaydjieva L, Karachanak-Yankova S, Karjalainen J, Kavanagh D, Keller MC, Kelly BJ, Kennedy JL, Khrunin A, Kim Y, Klovins J, Knowles JA, Konte B, Kucinskas V, Kucinskiene ZA, Kuzelova-Ptackova H, Kahler AK, Laurent C, Keong JL, Lee SH, Legge SE, Lerer B, Li M, Li T, Liang KY, Lieberman J, Limborska S, Loughland CM, Lubinski J, Lnnqvist J, Macek M Jr, Magnusson PK, Maher BS, Maier W, Mallet J, Marsal S, Mattheisen M, Mattingsdal M, McCarley RW, 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, Morris DW, Mors O, Mortensen PB, Murphy KC, Murray RM, Myin-Germeys I, Mller-Myhsok B, Nelis M, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nikitina-Zake L, Nisenbaum L, Nordin A, O'Callaghan E, O'Dushlaine C, O'Neill FA, Oh SY, Olincy A, Olsen L, Van Os J, Pantelis C, Papadimitriou GN, Papiol S, Parkhomenko E, Pato MT, Paunio T, Pejovic-Milovancevic M, Perkins DO, Pietilinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Sanders AR, Schall U, Schubert CR, Schulze TG, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Shi J, Sigurdsson E, Silagadze T, Silverman JM, Sim K, Slominsky P, Smoller JW, So HC, Spencer CC, Stahl EA, Stefansson H, Steinberg S, Stogmann E, Straub RE, Strengman E, Strohmaier J, Stroup TS, Subramaniam M, Suvisaari J, Svrakic DM, Szatkiewicz JP, Sderman E, Thirumalai S, Toncheva D, Tooney PA, Tosato S, Veijola J, Waddington J, Walsh D, Wang D, Wang Q, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wong EH, Wormley BK, Wu JQ, Xi HS, Zai CC, Zheng X, Zimprich F, Wray NR, Stefansson K, Visscher PM, Adolfsson R, Andreassen OA, Blackwood DH, Bramon E, Buxbaum JD, Børglum AD, Cichon S, Darvasi A, Domenici E, Ehrenreich H, Esko T, Gejman PV, Gill M, Gurling H, Hultman CM, Iwata N, Jablensky AV, Jonsson EG, Kendler KS, Kirov G, Knight J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, McCarroll SA, McQuillin A, Moran JL, Mortensen PB, Mowry BJ, Nthen MM, Ophoff RA, Owen MJ, Palotie A, Pato CN, Petryshen TL, Posthuma D, Rietschel M, Riley BP, Rujescu D, Sham PC, Sklar P, St Clair D, Weinberger DR, Wendland JR, Werge T, Daly MJ, Sullivan PF, O'Donovan MC, Kraft P, Hunter DJ, Adank M, Ahsan H, Aittomäki K, Baglietto L, Berndt S, Blomquist C, Canzian F, Chang-Claude J, Chanock SJ, Crisponi L, Czene K, Dahmen N, Silva Idos S, Easton D, Eliassen AH, Figueroa J, Fletcher O, Garcia-Closas M, Gaudet MM, Gibson L, Haiman CA, Hall P, Hazra A, Hein R, Henderson BE, Hofman A, Hopper JL, Irwanto A, Johansson M, Kaaks R, Kibriya MG, Lichtner P, Lindström S, Liu J, Lund E, Makalic E, Meindl A, Meijers-Heijboer H, Müller-Myhsok B, Muranen TA, Nevanlinna H, Peeters PH, Peto J, Prentice RL, Rahman N, Sánchez MJ, Schmidt DF, Schmutzler RK, Southey MC, Tamimi R, Travis R, Turnbull C, Uitterlinden AG, van der Luijt RB, Waisfisz Q, Wang Z, Whittemore AS, Yang R, Zheng W.

Author information

1
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark. Electronic address: bjarni.vilhjalmsson@gmail.com.
2
Queensland Brain Institute, University of Queensland, Brisbane, 4072 QLD, Australia; Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, 4101 QLD, Australia.
3
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
5
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Deptartment of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany.
7
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
8
Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
10
Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at University of Southern California, Los Angeles, CA 90089, USA.
11
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
12
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center of Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
13
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
14
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
15
Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center of Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
16
Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark.
17
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Translational NeuroPsychiatric Genomics, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
18
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
19
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
20
Department of Food and Agricultural Systems, University of Melbourne, Parkville, 3010 VIC, Australia; Biosciences Research Division, Department of Primary Industries, Bundoora, 3083 VIC, Australia.
21
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
22
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
23
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aprice@hsph.harvard.edu.

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.

PMID:
26430803
PMCID:
PMC4596916
DOI:
10.1016/j.ajhg.2015.09.001
[Indexed for MEDLINE]
Free PMC Article

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