Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Associations between potentially modifiable risk factors and Alzheimer disease: A mendelian randomization study

Østergaard, Søren D., Mukherjee, Shubhabrata, Sharp, Stephen J., Proitsi, Petroula, Lotta, Luca A., Day, Felix, Perry, John R. B., Boehme, Kevin L., Walter, Stefan, Kauwe, John S., Gibbons, Laura E., Alzheimer's Disease Genetics Consortium, EPIC-InterAct Consortium, Larson, Eric B., Powell, John F., Langenberg, Claudia, Crane, Paul K., Wareham, Nicholas J., Scott, Robert A., Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Gerrish, Amy, Hamshere, Marian L. ORCID: https://orcid.org/0000-0002-8990-0958, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Badarinarayan, Nandini ORCID: https://orcid.org/0000-0002-6944-748X, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 2015. Associations between potentially modifiable risk factors and Alzheimer disease: A mendelian randomization study. PLOS MEDICINE 12 (6) , e1001841. 10.1371/journal.pmed.1001841

Full text not available from this repository.

Abstract

BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Additional Information: Rebecca Sims, Amy Gerrish, Marian Hamshere, Valentina Escott-Price, Nandini Badarinarayan, Peter Holmans, Michael O'Donovan, Michael Owen and Julie Williams are collaborators on this article.
Publisher: PUBLIC LIBRARY SCIENCE
ISSN: 1549-1676
Date of Acceptance: 8 May 2015
Last Modified: 31 Oct 2022 10:40
URI: https://orca.cardiff.ac.uk/id/eprint/85641

Citation Data

Cited 123 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item