A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2,3,4,5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.
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UK Biobank analyses were conducted via application 7089 using a protocol approved by the Partners HealthCare Institutional Review Board. The analysis was supported by a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst funded by the National Institutes of Health (TR001100 to A.V.K.), a Junior Faculty Research Award from the National Lipid Association (to A.V.K.), the National Heart, Lung, and Blood Institute of the US National Institutes of Health under award numbers T32 HL007208 (to K.G.A.), K23HL114724 (to S.A.L.), R01HL139731 (to S.A.L.), RO1HL092577 (to P.T.E.), R01HL128914 (to P.T.E.), K24HL105780 (to P.T.E.), and RO1 HL127564 (to S.K.), the National Human Genome Research Institute of the US National Institutes of Health under award number 5UM1HG008895 (to E.S.L. and S.K.), the Doris Duke Charitable Foundation under award number 2014105 (to S.A.L.), the Foundation Leducq under award number 14CVD01 (to P.T.E.), and the Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital (to S.K.). The authors thank D. Altshuler (Vertex Pharmaceuticals, Boston, MA) for comments on an earlier version of this manuscript.
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medizinische genetik (2018)