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Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer’s disease: a Mendelian randomization study
Jin-Tai Yu
Huashan Hospital, Fudan University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7686-0547
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This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Alzheimer's Research and Therapy.
Background: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer’s disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.
Methods: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.
Results: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P>0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs) and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR)=0.959, 95% confidence interval (CI)=0.941-0.977, P=3.92×10-6], and overall use of AHMs (OR=0.961, 95% CI=0.944-0.978, P=5.74×10-6, SNPs=52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P>0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.
Conclusions: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.
Keywords
blood pressure, antihypertensive medications, Alzheimer’s disease, single nucleotide polymorphism, Mendelian randomization
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CURRENT STATUS: Published
Version 2
Posted 01 Feb, 2021
Published
On 09 Feb, 2021
No community comments so far
Editorial decision: Accept
On 31 Jan, 2021
Reviewer #2 agreed
On 30 Jan, 2021
Reviewers invited
Invitations sent on 30 Jan, 2021
Reviewer #1 agreed
On 30 Jan, 2021
Review #2 received
Received 30 Jan, 2021
Review #1 received
Received 30 Jan, 2021
Editor assigned
On 24 Jan, 2021
Submission checks complete
On 24 Jan, 2021
Editor invited
On 24 Jan, 2021
Version (no preprint)
Posted 16 Jan, 2021
Review #2 received
Received 16 Jan, 2021
Editorial decision: Minor Revision
On 16 Jan, 2021
Review #1 received
Received 10 Jan, 2021
Reviewer #2 agreed
On 09 Jan, 2021
Reviewers invited
Invitations sent on 09 Jan, 2021
Reviewer #1 agreed
On 09 Jan, 2021
Editor assigned
On 06 Jan, 2021
Submission checks complete
On 06 Jan, 2021
Editor invited
On 06 Jan, 2021
This version was not preprinted
No comments provided
Editorial decision: Major Revision
On 26 Dec, 2020
Review #1 received
Received 26 Dec, 2020
Review #2 received
Received 07 Dec, 2020
Reviewer #2 agreed
On 06 Dec, 2020
Reviewers invited
Invitations sent on 05 Dec, 2020
Reviewer #1 agreed
On 05 Dec, 2020
Editor assigned
On 30 Nov, 2020
Submission checks complete
On 30 Nov, 2020
Editor invited
On 30 Nov, 2020
First submitted
On 28 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
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This preprint is under consideration at Alzheimer's Research and Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer’s disease: a Mendelian randomization study
Jin-Tai Yu
Huashan Hospital, Fudan University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7686-0547
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 01 Feb, 2021
Published
On 09 Feb, 2021
No community comments so far
Editorial decision: Accept
On 31 Jan, 2021
Reviewer #2 agreed
On 30 Jan, 2021
Reviewers invited
Invitations sent on 30 Jan, 2021
Reviewer #1 agreed
On 30 Jan, 2021
Review #2 received
Received 30 Jan, 2021
Review #1 received
Received 30 Jan, 2021
Editor assigned
On 24 Jan, 2021
Submission checks complete
On 24 Jan, 2021
Editor invited
On 24 Jan, 2021
Version (no preprint)
Posted 16 Jan, 2021
Review #2 received
Received 16 Jan, 2021
Editorial decision: Minor Revision
On 16 Jan, 2021
Review #1 received
Received 10 Jan, 2021
Reviewer #2 agreed
On 09 Jan, 2021
Reviewers invited
Invitations sent on 09 Jan, 2021
Reviewer #1 agreed
On 09 Jan, 2021
Editor assigned
On 06 Jan, 2021
Submission checks complete
On 06 Jan, 2021
Editor invited
On 06 Jan, 2021
This version was not preprinted
No comments provided
Editorial decision: Major Revision
On 26 Dec, 2020
Review #1 received
Received 26 Dec, 2020
Review #2 received
Received 07 Dec, 2020
Reviewer #2 agreed
On 06 Dec, 2020
Reviewers invited
Invitations sent on 05 Dec, 2020
Reviewer #1 agreed
On 05 Dec, 2020
Editor assigned
On 30 Nov, 2020
Submission checks complete
On 30 Nov, 2020
Editor invited
On 30 Nov, 2020
First submitted
On 28 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Alzheimer's Research and Therapy.
Background: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer’s disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.
Methods: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.
Results: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P>0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs) and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR)=0.959, 95% confidence interval (CI)=0.941-0.977, P=3.92×10-6], and overall use of AHMs (OR=0.961, 95% CI=0.944-0.978, P=5.74×10-6, SNPs=52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P>0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.
Conclusions: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.
Figure 1
Figure 2
Figure 3
Figure 4