title: Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.
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.
authors.affiliation: 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.
authors.forename: Bjarni J
authors.initials: BJ
authors.lastname: Vilhjálmsson
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, 4072 QLD, Australia; Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, 4101 QLD, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Finucane
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: 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.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: 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.
authors.forename: Po-Ru
authors.initials: PR
authors.lastname: Loh
authors.affiliation: 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.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatia
authors.affiliation: 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.
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.affiliation: 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.
authors.forename: Tristan
authors.initials: T
authors.lastname: Hayeck
authors.affiliation: 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.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.affiliation: 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.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Pato
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pato
authors.affiliation: 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.
authors.forename: Rulla
authors.initials: R
authors.lastname: Tamimi
authors.affiliation: 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.
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.affiliation: 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.
authors.forename: Gillian
authors.initials: G
authors.lastname: Belbin
authors.affiliation: 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.
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.affiliation: Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Mikkel H
authors.initials: MH
authors.lastname: Schierup
authors.affiliation: 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.
authors.forename: Philip
authors.initials: P
authors.lastname: De Jager
authors.affiliation: 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.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: 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.
authors.forename: Steve
authors.initials: S
authors.lastname: McCarroll
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.affiliation: 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.
authors.forename: Shaun
authors.initials: S
authors.lastname: Purcell
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chasman
authors.affiliation: 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neale
authors.affiliation: Department of Food and Agricultural Systems, University of Melbourne, Parkville, 3010 VIC, Australia; Biosciences Research Division, Department of Primary Industries, Bundoora, 3083 VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Goddard
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, 4072 QLD, Australia; Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, 4101 QLD, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.affiliation: 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.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008962:Models, Theoretical; D020412:Multifactorial Inheritance / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D040641:Quantitative Trait Loci; D012559:Schizophrenia / Q000235:genetics*