Polygenic overlap between kidney function and large artery atherosclerotic stroke

Holliday, Elizabeth G. and Traylor, Matthew and Malik, Rainer and Bevan, Stephen and Maguire, Jane and Koblar, Simon A. and Sturm, Jonathan and Hankey, Graeme J. and Oldmeadow, Christopher and McEvoy, Mark and Sudlow, Cathie and Rothwell, Peter M. and Coresh, Josef and Hamet, Pavel and Tremblay, Johanne and Turner, Stephen T. and de Andrade, Mariza and Rao, Madhumathi and Schmidt, Reinhold and Crick, Peter A. and Robino, Antonietta and Peralta, Carmen A. and Jukema, J. Wouter and Mitchell, Paul and Rosas, Sylvia E. and Wang, Jie Jin and Scott, Rodney J. and Dichgans, Martin and Mitchell, Braxton D. and Kao, W.H. Linda and Fox, Caroline S. and Levi, Christopher and Attia, John and Markus, Hugh S. (2014) Polygenic overlap between kidney function and large artery atherosclerotic stroke. Stroke, 45 (12). pp. 3508-3513. ISSN 0039-2499

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Background and Purpose—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.

Methods—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.

Results—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).

Conclusions—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.

Keywords:Genetic epidemiology, Kidney, Stroke, NotOAChecked
Subjects:C Biological Sciences > C431 Medical Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:19441
Deposited On:06 Nov 2015 11:10

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