Polygenic overlap between kidney function and large artery atherosclerotic stroke.
Holliday EG., Traylor M., Malik R., Bevan S., Maguire J., Koblar SA., Sturm J., Hankey GJ., Oldmeadow C., McEvoy M., Sudlow C., Rothwell PM., Coresh J., Hamet P., Tremblay J., Turner ST., de Andrade M., Rao M., Schmidt R., Crick PA., Robino A., Peralta CA., Jukema JW., Mitchell P., Rosas SE., Wang JJ., Scott RJ., Dichgans M., Mitchell BD., Kao WH., Fox CS., Levi C., Attia J., Markus HS., CKDGen Consortium and the International Stroke Genetics Consortium None.
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.