Genetic overlap and causal inferences between kidney function and cerebrovascular disease
Citation Manager Formats
Make Comment
See Comments

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Objective Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.
Methods We 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.
Results A 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.
Conclusions Impaired 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.
Glossary
- CES=
- cardioembolic stroke;
- CI=
- confidence interval;
- CKD=
- chronic kidney disease;
- eGFR=
- estimated glomerular filtration rate;
- GWAS=
- genome-wide association studies;
- ICH=
- intracerebral hemorrhage;
- IS=
- ischemic stroke;
- ISGC=
- International Stroke Genetic Consortium;
- IVW=
- inverse variance weighted;
- LAS=
- large artery atherosclerotic stroke;
- LD=
- linkage disequilibrium;
- MR=
- Mendelian randomization;
- OR=
- odds ratio;
- PPA=
- posterior probabilities of association;
- PRS=
- polygenic risk scoring;
- SBP=
- systolic blood pressure;
- SNP=
- single nucleotide polymorphism;
- SVS=
- small vessel stroke;
- UACR=
- urinary albumin-to-creatinine ratio;
- WMH=
- white matter hyperintensity
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Editorial, page 1060
- Received May 15, 2019.
- Accepted in final form January 26, 2020.
- © 2020 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
For assistance, please contact:
AAN Members (800) 879-1960 or (612) 928-6000 (International)
Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international)
Sign Up
Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here
Purchase
Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed.
Disputes & Debates: Rapid online correspondence
NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
- Stay timely. Submit only on articles published within the last 8 weeks.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- 200 words maximum.
- 5 references maximum. Reference 1 must be the article on which you are commenting.
- 5 authors maximum. Exception: replies can include all original authors of the article.
- Submitted comments are subject to editing and editor review prior to posting.