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Cited by 1,303Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenetic and phenotypic traits in livestock

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

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Vilhjálmsson, Bjarni J., Yang, Jian, Finucane, Hilary K., Gusev, Alexander, Lindström, Sara, Ripke, Stephan, Genovese, Giulio, Loh, Po-Ru +394 more·2015·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2015.09.001PMC PMC4596916

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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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  • PRS are many-fold more accurate in European ancestry individuals than in others, and this disparity is the major ethical and scientific challenge surrounding clinical implementation.

    “However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [15]

    The Results (p. 8) report lower absolute prediction accuracy in African- and Asian-ancestry schizophrenia validation samples, and the Discussion (p. 9) calls for improving prediction in diverse populations. The paper does not establish a many-fold difference across PRSs generally or characterize that disparity as the major ethical and scientific challenge to clinical implementation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The scientific basis of the imbalance in PRS accuracy has been demonstrated theoretically, in simulations, and empirically across many traits and diseases.

    “The scientific basis of this imbalance has been demonstrated theoretically, in simulations, and empirically across many traits and diseases11–22.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [15]

    The Discussion (p. 9) reports lower absolute PRS prediction accuracy in non-European than European validation samples, and the results (p. 8) include African- and Asian-descent schizophrenia samples. But the paper’s theory and simulations concern accuracy gains from modeling linkage disequilibrium, not a theoretical and simulated demonstration of the population-level imbalance across many traits and diseases. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A common variant predictor explained 15% of the variance in schizophrenia liability in this cohort.

    “While a predictor based on common variants24,109 explained 15% of the variance in schizophrenia liability in this cohort”

    From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [109]

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  1. [7]7. [Bush, W.S., Sawcer, S.J., de Jager, P.L., Oksenberg, J.R., McCauley, J.L., Pericak-Vance, M.A., and Haines, J.L.; Interna-](http://refhub.elsevier.com/S0002-9297(15)00365-1/sref7)

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Vilhjálmsson, B. J., Yang, J., Finucane, H. K., Gusev, A., Lindström, S., Ripke, S., Genovese, G., Loh, P.-R., Bhatia, G., Do, R., Hayeck, T., Won, H.-H., Kathiresan, S., Pato, M., Pato, C., Tamimi, R., Stahl, E., Zaitlen, N., Pasaniuc, B., Belbin, G., Kenny, E. E., Schierup, M. H., De Jager, P., Patsopoulos, N. A., McCarroll, S., Daly, M., Purcell, S., Chasman, D., Neale, B., Goddard, M., Visscher, P. M., Kraft, P., Patterson, N., Price, A. L., Ripke, S., Neale, B. M., Corvin, A., Walters, J. T. R., Farh, K.-H., Holmans, P. A., Lee, P., Bulik-Sullivan, B., Collier, D. A., Huang, H., Pers, T. H., Agartz, I., Agerbo, E., Albus, M., Alexander, M., Amin, F., Bacanu, S. A., Begemann, M., Belliveau, R. A., Bene, J., Bergen, S. E., Bevilacqua, E., Bigdeli, T. B., Black, D. W., Bruggeman, R., Buccola, N. G., Buckner, R. L., Byerley, W., Cahn, W., Cai, G., Campion, D., Cantor, R. M., Carr, V. J., Carrera, N., Catts, S. V., Chambert, K. D., Chan, R. C. K., Chen, R. Y. L., Chen, E. Y. H., Cheng, W., Cheung, E. F. C., Chong, S. A., Cloninger, C. R., Cohen, D., Cohen, N., Cormican, P., Craddock, N., Crowley, J. J., Curtis, D., Davidson, M., Davis, K. L., Degenhardt, F., Del Favero, J., DeLisi, L. E., 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, A. H., Farrell, M. S., Frank, J., Franke, L., Freedman, R., Freimer, N. B., Friedl, M., Friedman, J. I., Fromer, M., Genovese, G., Georgieva, L., Gershon, E. S., Giegling, I., Giusti-Rodrguez, P., Godard, S., Goldstein, J. I., Golimbet, V., Gopal, S., Gratten, J., Grove, J., de Haan, L., Hammer, C., Hamshere, M. L., Hansen, M., Hansen, T., Haroutunian, V., Hartmann, A. M., Henskens, F. A., Herms, S., Hirschhorn, J. N., Hoffmann, P., Hofman, A., Hollegaard, M. V., Hougaard, D. M., Ikeda, M., Joa, I., Julia, A., Kahn, R. S., Kalaydjieva, L., Karachanak-Yankova, S., Karjalainen, J., Kavanagh, D., Keller, M. C., Kelly, B. J., Kennedy, J. L., Khrunin, A., Kim, Y., Klovins, J., Knowles, J. A., Konte, B., Kucinskas, V., Kucinskiene, Z. A., Kuzelova-Ptackova, H., Kahler, A. K., Laurent, C., Keong, J. L. C., Lee, S. H., Legge, S. E., Lerer, B., Li, M., Li, T., Liang, K.-Y., Lieberman, J., Limborska, S., Loughland, C. M., Lubinski, J., Lnnqvist, J., Macek, M., Magnusson, P. K. E., Maher, B. S., Maier, W., Mallet, J., Marsal, S., Mattheisen, M., Mattingsdal, M., McCarley, R. W., McDonald, C., McIntosh, A. M., Meier, S., Meijer, C. J., Melegh, B., Melle, I., Mesholam-Gately, R. I., Metspalu, A., Michie, P. T., Milani, L., Milanova, V., Mokrab, Y., Morris, D. W., Mors, O., Mortensen, P. B., Murphy, K. C., Murray, R. M., Myin-Germeys, I., Mller-Myhsok, B., Nelis, M., Nenadic, I., Nertney, D. A., Nestadt, G., Nicodemus, K. K., Nikitina-Zake, L., Nisenbaum, L., Nordin, A., O’Callaghan, E., O’Dushlaine, C., O’Neill, F. A., Oh, S.-Y., Olincy, A., Olsen, L., Van Os, J., Pantelis, C., Papadimitriou, G. N., Papiol, S., Parkhomenko, E., Pato, M. T., Paunio, T., Pejovic-Milovancevic, M., Perkins, D. O., Pietilinen, O., Pimm, J., Pocklington, A. J., Powell, J., Price, A., Pulver, A. E., Purcell, S. M., Quested, D., Rasmussen, H. B., Reichenberg, A., Reimers, M. A., Richards, A. L., Roffman, J. L., Roussos, P., Ruderfer, D. M., Salomaa, V., Sanders, A. R., Schall, U., Schubert, C. R., Schulze, T. G., Schwab, S. G., Scolnick, E. M., Scott, R. J., Seidman, L. J., Shi, J., Sigurdsson, E., Silagadze, T., Silverman, J. M., Sim, K., Slominsky, P., Smoller, J. W., So, H.-C., Spencer, C. C. A., Stahl, E. A., Stefansson, H., Steinberg, S., Stogmann, E., Straub, R. E., Strengman, E., Strohmaier, J., Stroup, T. S., Subramaniam, M., Suvisaari, J., Svrakic, D. M., Szatkiewicz, J. P., Sderman, E., Thirumalai, S., Toncheva, D., Tooney, P. A., Tosato, S., Veijola, J., Waddington, J., Walsh, D., Wang, D., Wang, Q., Webb, B. T., Weiser, M., Wildenauer, D. B., Williams, N. M., Williams, S., Witt, S. H., Wolen, A. R., Wong, E. H. M., Wormley, B. K., Wu, J. Q., Xi, H. S., Zai, C. C., Zheng, X., Zimprich, F., Wray, N. R., Stefansson, K., Visscher, P. M., Adolfsson, R., Andreassen, O. A., Blackwood, D. H. R., Bramon, E., Buxbaum, J. D., Børglum, A. D., Cichon, S., Darvasi, A., Domenici, E., Ehrenreich, H., Esko, T., Gejman, P. V., Gill, M., Gurling, H., Hultman, C. M., Iwata, N., Jablensky, A. V., Jonsson, E. G., Kendler, K. S., Kirov, G., Knight, J., Lencz, T., Levinson, D. F., Li, Q. S., Liu, J., Malhotra, A. K., McCarroll, S. A., McQuillin, A., Moran, J. L., Mortensen, P. B., Mowry, B. J., Nthen, M. M., Ophoff, R. A., Owen, M. J., Palotie, A., Pato, C. N., Petryshen, T. L., Posthuma, D., Rietschel, M., Riley, B. P., Rujescu, D., Sham, P. C., Sklar, P., St. Clair, D., Weinberger, D. R., Wendland, J. R., Werge, T., Daly, M. J., Sullivan, P. F., O’Donovan, M. C., Kraft, P., Hunter, D. J., Adank, M., Ahsan, H., Aittomäki, K., Baglietto, L., Berndt, S., Blomquist, C., Canzian, F., Chang-Claude, J., Chanock, S. J., Crisponi, L., Czene, K., Dahmen, N., Silva, I. D. S., Easton, D., Eliassen, A. H., Figueroa, J., Fletcher, O., Garcia-Closas, M., Gaudet, M. M., Gibson, L., Haiman, C. A., Hall, P., Hazra, A., Hein, R., Henderson, B. E., Hofman, A., Hopper, J. L., Irwanto, A., Johansson, M., Kaaks, R., Kibriya, M. G., Lichtner, P., Lindström, S., Liu, J., Lund, E., Makalic, E., Meindl, A., Meijers-Heijboer, H., Müller-Myhsok, B., Muranen, T. A., Nevanlinna, H., Peeters, P. H., Peto, J., Prentice, R. L., Rahman, N., Sánchez, M. J., Schmidt, D. F., Schmutzler, R. K., Southey, M. C., Tamimi, R., Travis, R., Turnbull, C., Uitterlinden, A. G., van der Luijt, R. B., Waisfisz, Q., Wang, Z., Whittemore, A. S., Yang, R., & Zheng, W.
Affiliations
  • Broad Institute (US)
  • Translational Research Institute (AU)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of California, San Francisco (US)
  • Aarhus University (DK)
  • Brigham and Women's Hospital (US)
  • The University of Melbourne (AU)
  • Harvard University (US)
  • University of Southern California (US)
Corresponding author
Vilhjálmsson, Bjarni J.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2015-10
Volume
97
Issue
4
Pages
576-592
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2015.09.001
PMC
PMC4596916
OpenAlex
W2169795969
Cited by
1,303
References
72
Citations by year
2026: 69 · 2025: 116 · 2024: 129 · 2023: 151 · 2022: 195 · 2021: 211 · 2020: 160 · 2019: 107 · 2018: 69 · 2017: 54 · 2016: 34 · 2015: 6
FWCI
37.35
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • Lancaster EPrints (Lancaster University) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • EPubDev Repository (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • Iris (University of Trento) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • GRO (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • RUNE (Research UNE) (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Hertz Foundation
  • Wellcome Trust (104036, 076113)
  • Lundbeckfonden (R155-2014-1724)
  • Danmarks Frie Forskningsfond
  • National Institutes of Health (CA148065)
  • Medical Research Council (MR/L023784/2, MR/L010305/1, MR/L023784/1)
  • National Heart, Lung, and Blood Institute (K25HL121295)
  • National Institute of Mental Health (R01MH085548)
  • National Cancer Institute (R03CA173785, U19CA148065, P01CA134294, R35CA197449)
  • National Institute of General Medical Sciences (R01GM105857, P01GM099568)
  • National Institute of Environmental Health Sciences (T32ES007142)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
polygenic risk score, linkage disequilibrium, effect size estimation, schizophrenia, multiple sclerosis, prediction accuracy
MeSH terms
Genotype, Humans, Models, Theoretical, Multiple Sclerosis, Phenotype, Prognosis, Schizophrenia, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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