Journal article

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Bjarni J Vilhjalmsson, Jian Yang, Hilary K Finucane, Alexander Gusev, Sara Lindstrom, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin Show all

AMERICAN JOURNAL OF HUMAN GENETICS | CELL PRESS | Published : 2015

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. Accordi..

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Grants

Awarded by NIH


Awarded by Danish Council for Independent Research


Awarded by Wellcome Trust


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Awarded by Lundbeck Foundation


Awarded by Medical Research Council


Funding Acknowledgements

We thank Shamil Sunayev, Brendan Bulik-Sullivan, Liming Liang, Naomi Wray, Daniel Sorensen, and Esben Agerbo for useful discussions. We would also like to thank Toni Clarke for useful comments on the software. This research was supported by NIH grants R01 GM105857, R03 CA173785, and U19 CA148065-01. B.J.V. was supported by Danish Council for Independent Research grant DFF-1325-0014. H.K.F. was supported by the Fannie and John Hertz Foundation. This study made use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the WTCCC data is available at www.wtccc.org.uk. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113.