Genetic overlap and causal inferences between kidney function and cerebrovascular disease
| Autor: | R. Malik, Christopher D. Anderson, Martin Dichgans, Jonathan Rosand, Sandro Marini, Jaeyoon Chung, Jonathan Henry, Marios K. Georgakis |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Multifactorial Inheritance Linkage disequilibrium medicine.medical_specialty genetics [Cerebrovascular Disorders] Renal function Genome-wide association study Kidney Kidney Function Tests Risk Assessment Linkage Disequilibrium 03 medical and health sciences 0302 clinical medicine Internal medicine Mendelian randomization medicine Humans Genetic Predisposition to Disease physiopathology [Kidney] ddc:610 Renal Insufficiency Chronic physiopathology [Cerebral Small Vessel Diseases] Stroke physiopathology [Stroke] business.industry physiopathology [Cerebrovascular Disorders] Odds ratio medicine.disease Magnetic Resonance Imaging Hyperintensity Cerebrovascular Disorders 030104 developmental biology Cerebral Small Vessel Diseases complications [Renal Insufficiency Chronic] genetics [Cerebral Small Vessel Diseases] Neurology (clinical) business 030217 neurology & neurosurgery Genome-Wide Association Study Glomerular Filtration Rate Kidney disease |
| Zdroj: | Neurology 94(24), e2581-e2591 (2020). doi:10.1212/WNL.0000000000009642 |
| ISSN: | 1526-632X 0028-3878 |
| DOI: | 10.1212/wnl.0000000000009642 |
| Popis: | ObjectiveLeveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.MethodsWe used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization.ResultsA PRS for lower eGFR was associated with higher large artery stroke (LAS) risk (p = 1 × 10−4). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38–3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12–4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH.ConclusionsImpaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|