Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Neurology: Clinical Practice Accelerator
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
    • UDDA Revision Series
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Diversity, Equity, & Inclusion (DEI)
    • Neurology: Clinical Practice Accelerator
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
    • UDDA Revision Series
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

April 2019; 5 (2) EditorialOpen Access

Unraveling the genetic complexity of Alzheimer disease with Mendelian Randomization

Sara Bandres-Ciga, Faraz Faghri
First published March 7, 2019, DOI: https://doi.org/10.1212/NXG.0000000000000313
Sara Bandres-Ciga
From the Molecular Genetics Section (S.B.-C., F.F.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Instituto de Investigación Biosanitaria de Granada (S.B.-C.), Granada, Spain; and Department of Computer Science (F.F.), University of Illinois at Urbana-Champaign, Urbana.
PhD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Faraz Faghri
From the Molecular Genetics Section (S.B.-C., F.F.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Instituto de Investigación Biosanitaria de Granada (S.B.-C.), Granada, Spain; and Department of Computer Science (F.F.), University of Illinois at Urbana-Champaign, Urbana.
MS
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Unraveling the genetic complexity of Alzheimer disease with Mendelian Randomization
Sara Bandres-Ciga, Faraz Faghri
Neurol Genet Apr 2019, 5 (2) e313; DOI: 10.1212/NXG.0000000000000313

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
708

Share

  • Article
  • Info & Disclosures
Loading

Genome-wide association studies (GWASs) have changed the way we conceive human genetics and have led to the discovery of thousands of risk variants involved in disease etiology. However, despite tremendous advances made in understanding the genetic architecture underlying disease, there remains an underinvestigated component of risk, namely phenotypic traits that can predispose or protect individuals to disease. The availability of large amounts of GWAS data affords the opportunity to investigate the relationship between myriad traits.1

In the current issue of Neurology® Genetics, Raghavan et al.2 aim at determining the putative causal relationship between educational attainment and Alzheimer disease (AD). The authors use Mendelian Randomization, the gold standard for causality in genetic studies, as a statistical approach that uses genetic data in the form of SNPs to study whether an exposure exerts a causal effect in an outcome. This promising methodology sits at the interface between observational epidemiology and interventional trials and aims at addressing the question of whether an observational association between a risk or protective factor and a disease of interest is consistent with a causal effect by focusing usually only on genome-wide significant SNPs. One of the key strengths of this method is that it relies on genetic variants that are fixed at conception and remain constant over the lifespan of an individual and that are randomized during gametogenesis, which means that genetic variants are not associated with all the confounder factors that affect an observational study.3

In a simple way, SNPs genome-wide associated with a certain exposure modify the risk of that exposure, which in turn affects the disease of interest. Raghavan et al. not only consider SNP genome-wide related to educational attainment as instrumental variables but also use genetic regions surrounding individually associated SNPs to nominate genes that might contribute to the disease.

The authors identify a causal inverse relationship between educational attainment and AD and demonstrate that an increase of 4.2 years of educational attainment is associated with 37% reduction in AD, exerting a notable protective effect. When focusing on individual loci, the authors identify 6 regions that significantly replicate the causal association and nominate the following genes: the leucine-rich repeat-containing 7 (LRCC7), the prostaglandin E receptor 3 (PTGER3), and the neuronal growth regulator precursor (NEGR1) genes as the main drivers of this relationship.

Mendelian Randomization has the potential to significantly contribute to our understanding of environmental and protective factors in Alzheimer disease; however, this method depends on assumptions, and the plausibility of these assumptions must be assessed. To verify the consistency of their findings, the authors perform a set of sensitivity analyses to account for confounding effects that might be violating any core assumption. No evidence of reverse causation, horizontal pleiotropy, or heterogeneity is identified.

The reported findings should be interpreted in the context of existing evidence from other research studies using different designs, and clinical guidelines should not be elaborated uniquely based on Mendelian Randomization results. To make a definite conclusion that might be helpful from the clinical perspective to guide disease prevention, replicating these findings in non-European populations with variable educational background and experiences remains key.

Author contributions

Both authors contributed equally to the initial manuscript preparation, manuscript editing, and commentary.

Study funding

No targeted funding reported.

Disclosure

S. Bandres-Ciga and F. Faghri report no disclosures. Disclosures available: at Neurology.org/NG.

Footnotes

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • See page e310

  • Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Buniello A,
    2. MacArthur JAL,
    3. Cerezo M, et al
    . The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 2019;47:D1005–D1012.
    OpenUrl
  2. 2.↵
    1. Raghavan N,
    2. Vardarajan B,
    3. Mayeux R
    . Genomic variation in educational attainment modifies Alzheimer disease risk. Neurol Genet 2019;5:e310. doi: 10.1212/NXG.0000000000000310.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Davey Smith G,
    2. Hemani G
    . Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014;23:R89–R98.
    OpenUrlCrossRefPubMed

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Author contributions
    • Study funding
    • Disclosure
    • Footnotes
    • References
  • Info & Disclosures
Advertisement

Association Between Fluctuations in Blood Lipid Levels Over Time With Incident Alzheimer Disease and Alzheimer Disease–Related Dementias

Dr. Sevil Yaşar and Dr. Behnam Sabayan

► Watch

Related Articles

  • Genomic variation in educational attainment modifies Alzheimer disease risk

Topics Discussed

  • All Genetics
  • All Neuropsychology/Behavior
  • Alzheimer disease

Alert Me

  • Alert me when eletters are published

Recommended articles

  • Article
    Genomic variation in educational attainment modifies Alzheimer disease risk
    Neha S. Raghavan, Badri Vardarajan, Richard Mayeux et al.
    Neurology: Genetics, February 11, 2019
  • Article
    Genetically decreased vitamin D and risk of Alzheimer disease
    Lauren E. Mokry, Stephanie Ross, John A. Morris et al.
    Neurology, November 16, 2016
  • Article
    Risky behaviors and Parkinson disease
    A mendelian randomization study
    Sandeep Grover, Christina M. Lill, Meike Kasten et al.
    Neurology, September 16, 2019
  • Article
    Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes
    Mendelian randomization study
    Susanna C. Larsson, Robert A. Scott, Matthew Traylor et al.
    Neurology, June 30, 2017
Neurology Genetics: 9 (6)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise