Polygenic overlap between kidney function and large artery atherosclerotic stroke

International Stroke Genetics Consortium

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3508-3513
Number of pages6
JournalStroke
Volume45
Issue number12
DOIs
StatePublished - Dec 11 2014

Fingerprint

Arteries
Stroke
Kidney
Creatinine
Albumins
Atherosclerosis
Cystatin C
Genome-Wide Association Study
Glomerular Filtration Rate
Single Nucleotide Polymorphism
Germany
Meta-Analysis
Epidemiologic Studies
Serum

Keywords

  • Genetic epidemiology
  • Kidney
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Medicine(all)

Cite this

Polygenic overlap between kidney function and large artery atherosclerotic stroke. / International Stroke Genetics Consortium.

In: Stroke, Vol. 45, No. 12, 11.12.2014, p. 3508-3513.

Research output: Contribution to journalArticle

International Stroke Genetics Consortium. / Polygenic overlap between kidney function and large artery atherosclerotic stroke. In: Stroke. 2014 ; Vol. 45, No. 12. pp. 3508-3513.
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abstract = "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",
author = "{International Stroke Genetics Consortium} and Holliday, {Elizabeth G.} and Matthew Traylor and Rainer Malik and Stephen Bevan and Jane Maguire and Koblar, {Simon A.} and Jonathan Sturm and Hankey, {Graeme J.} and Christopher Oldmeadow and Mark McEvoy and Cathie Sudlow and Rothwell, {Peter M.} and Josef Coresh and Pavel Hamet and Johanne Tremblay and Turner, {Stephen T} and {De Andrade}, Mariza and Madhumathi Rao and Reinhold Schmidt and Crick, {Peter A.} and Antonietta Robino and Peralta, {Carmen A.} and Jukema, {J. Wouter} and Paul Mitchell and Rosas, {Sylvia E.} and Wang, {Jie Jin} and Scott, {Rodney J.} and Martin Dichgans and Mitchell, {Braxton D.} and Kao, {W. H Linda} and Fox, {Caroline S.} and Christopher Levi and John Attia and Markus, {Hugh S.}",
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T1 - Polygenic overlap between kidney function and large artery atherosclerotic stroke

AU - International Stroke Genetics Consortium

AU - Holliday, Elizabeth G.

AU - Traylor, Matthew

AU - Malik, Rainer

AU - Bevan, Stephen

AU - Maguire, Jane

AU - Koblar, Simon A.

AU - Sturm, Jonathan

AU - Hankey, Graeme J.

AU - Oldmeadow, Christopher

AU - McEvoy, Mark

AU - Sudlow, Cathie

AU - Rothwell, Peter M.

AU - Coresh, Josef

AU - Hamet, Pavel

AU - Tremblay, Johanne

AU - Turner, Stephen T

AU - De Andrade, Mariza

AU - Rao, Madhumathi

AU - Schmidt, Reinhold

AU - Crick, Peter A.

AU - Robino, Antonietta

AU - Peralta, Carmen A.

AU - Jukema, J. Wouter

AU - Mitchell, Paul

AU - Rosas, Sylvia E.

AU - Wang, Jie Jin

AU - Scott, Rodney J.

AU - Dichgans, Martin

AU - Mitchell, Braxton D.

AU - Kao, W. H Linda

AU - Fox, Caroline S.

AU - Levi, Christopher

AU - Attia, John

AU - Markus, Hugh S.

PY - 2014/12/11

Y1 - 2014/12/11

N2 - 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.

AB - 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.

KW - Genetic epidemiology

KW - Kidney

KW - Stroke

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