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Stroke. 2014 Dec;45(12):3508-13. doi: 10.1161/STROKEAHA.114.006609. Epub 2014 Oct 28.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

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From the School of Medicine and Public Health (E.G.H., J.S., M.M., J.A.) and School of Nursing and Midwifery (J.M.), University of Newcastle, Australia; Clinical Research Design, IT and Statistical Support Unit (E.G.H., C.O., J.A.), Hunter Medical Research Institute (J.M., R.J.S., C.L.), Newcastle, Australia; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Stroke Research Program, School of Medicine and Adelaide Center for Neuroscience Research, University of Adelaide, Australia (S.A.K.); Neurology Department, Gosford Hospital, Australia (J.S.); School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia (G.J.H.); Neurology Department, Sir Charles Gairdner Hospital, Perth, Australia (G.J.H.); Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, UK (P.M.R.); Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (J.C., W.H.L.K.); The University of Montreal Hospital Health Centre, Research Centre, University of Montreal, Montreal, Canada (P.H., J.T.); Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.) and Division of Biomedical Statistics and Informatics (M.d.A.), Mayo Clinic, Rochester, MN; Division of Nephrology/Tufts Evidence Practice Center, Tufts University School of Medicine, Boston, MA (M.R.); Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Austria (R.S.); Division of Regulatory Systems and Risk Management, Department of Defense, Australia (P.A.C.); Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy (A.R.); Division of Nephrology, University of California San Francisco Scho



Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes.


Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease.


Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02).


This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.


genetic epidemiology; kidney; stroke

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