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About this Publication
Title
Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.
Pubmed ID
26430803 (View this publication on the PubMed website)
Publication
Am. J. Hum. Genet. 2015 Oct; Volume 97 (Issue 4): Pages 576-92
Authors
Vilhjálmsson BJ, Yang J, Finucane HK, Gusev A, Lindström S, Ripke S, Genovese G, Loh PR, Bhatia G, Do R, Hayeck T, Won HH, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Kathiresan S, Pato M, Pato C, Tamimi R, Stahl E, Zaitlen N, Pasaniuc B, ...show more Belbin G, Kenny EE, Schierup MH, De Jager P, Patsopoulos NA, McCarroll S, Daly M, Purcell S, Chasman D, Neale B, Goddard M, Visscher PM, Kraft P, Patterson N, Price AL
Affiliations
  • 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.
  • Queensland Brain Institute, University of Queensland, Brisbane, 4072 QLD, Australia; Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, 4101 QLD, Australia.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Department of Psychiatry and Behavioral Sciences, Keck School of Medicine at University of Southern California, Los Angeles, CA 90089, USA.
...show more
  • 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.
  • 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.
  • Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 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.
  • Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark.
  • 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.
  • 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 Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
  • Department of Food and Agricultural Systems, University of Melbourne, Parkville, 3010 VIC, Australia; Biosciences Research Division, Department of Primary Industries, Bundoora, 3083 VIC, Australia.
  • 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.
  • Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 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.

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