University of Oulu

Karhunen, V., Bakker, M. K., Ruigrok, Y. M., Gill, D., & Larsson, S. C. (2021). Modifiable Risk Factors for Intracranial Aneurysm and Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study. Journal of the American Heart Association 10(22), e022277,

Modifiable risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage : a Mendelian randomization study

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Author: Karhunen, Ville1,2,3; Bakker, Mark K.4; Ruigrok, Ynte M.4;
Organizations: 1Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
2Research Unit of Mathematical Sciences, University of Oulu, Finland
3Center for Life Course Health Research, University of Oulu, Finland
4Department of Neurology and Neurosurgery, , University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands
5Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
6Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
7Novo Nordisk Research Centre Oxford, Oxford, United Kingdom
8Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
9Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
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Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-11-22


Background: The aim of this study was to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage using Mendelian randomization.

Methods and Results: Summary statistical data for the genetic associations with the modifiable risk factors and the outcomes were obtained from meta‐analyses of genome‐wide association studies. The inverse‐variance weighted method was used as the main Mendelian randomization analysis, with additional sensitivity analyses conducted using methods more robust to horizontal pleiotropy. Genetic predisposition to smoking, insomnia, and higher blood pressure was associated with an increased risk of both intracranial aneurysm and aneurysmal subarachnoid hemorrhage. For intracranial aneurysm, the odds ratios were 3.20 (95% CI, 1.93–5.29) per SD increase in smoking index, 1.24 (95% CI, 1.10–1.40) per unit increase in log‐odds of insomnia, and 2.92 (95% CI, 2.49–3.43) per 10 mm Hg increase in diastolic blood pressure. In addition, there was weak evidence for associations of genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower low‐density lipoprotein cholesterol levels with higher risk of intracranial aneurysm and aneurysmal subarachnoid hemorrhage, with 95% CI overlapping the null for at least 1 of the outcomes. All results were consistent in sensitivity analyses.

Conclusions: This Mendelian randomization study suggests that smoking, insomnia, and high blood pressure are major risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

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Series: Journal of the American Heart Association
ISSN: 2047-9980
ISSN-E: 2047-9980
ISSN-L: 2047-9980
Volume: 10
Issue: 22
Article number: e022277
DOI: 10.1161/JAHA.121.022277
Type of Publication: A1 Journal article – refereed
Field of Science: 3142 Public health care science, environmental and occupational health
3121 General medicine, internal medicine and other clinical medicine
Funding: Gill and Karhunen are supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. Karhunen is supported by the Academy of Finland Project 312123, and European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 848158. Gill is supported by a National Institute for Health Research Clinical Lectureship at St. George's, University of London (CL‐2020‐16‐001). Larsson acknowledges research support from the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018‐00123), the Swedish Heart‐Lung Foundation (Hjärt‐Lungfonden, 20190247), and the Swedish Research Council (Vetenskapsrådet, 2019‐00977). Bakker was supported by the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation, CVON2015‐08 ERASE. Ruigrok received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (PRYSM, grant agreement No. 852173).
EU Grant Number: (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Academy of Finland Grant Number: 312123
Detailed Information: 312123 (Academy of Finland Funding decision)
Copyright information: © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.