Evidence map›Paper›PMID 26449541›Full record

SynthesisAlzheimer's & dementia : the journal of the Alzheimer's Association2016

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

Mark T W Ebbert, Kevin L Boehme, Mark E Wadsworth, Lyndsay A Staley, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Genetics Consortium, Shubhabrata Mukherjee, Paul K Crane, Perry G Ridge, John S K Kauwe

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed, 1 pooled it
2.8field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 1 synthesis or guideline pooled it, 23 citations in OpenAlex.

  1. Association between CLU gene rs11136000 polymorphism and Alzheimer's disease: an updated meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2018
    Pooled it
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Mark T W EbbertDepartment of Biology, Brigham Young University, Provo, UT, USA.
Kevin L BoehmeDepartment of Biology, Brigham Young University, Provo, UT, USA.
Mark E WadsworthDepartment of Biology, Brigham Young University, Provo, UT, USA.
Lyndsay A StaleyDepartment of Biology, Brigham Young University, Provo, UT, USA.
Alzheimer's Disease Neuroimaging Initiative
Alzheimer's Disease Genetics Consortium
Shubhabrata MukherjeeDepartment of Medicine, University of Washington, Seattle, WA, USA.
Paul K CraneDepartment of Medicine, University of Washington, Seattle, WA, USA.
Perry G RidgeDepartment of Biology, Brigham Young University, Provo, UT, USA.
John S K KauweDepartment of Biology, Brigham Young University, Provo, UT, USA. Electronic address: kauwe@byu.edu.
Brigham Young University · USUniversity of Washington · US

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2M
Project-005UL1TR001445 · NCATS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI BREDELLA, MIRIAM ANTOINETTE, HOCHMAN, JUDITH S · 2015 to 2025
$103.5M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI JAYADEY, SUMAN · 1985 to 2019
$57.2M
VIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4M
WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1M
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1M
CIHRHoward Hughes Medical InstituteMedical Research CouncilNCATS NIH HHS UL1 TR001445NCI NIH HHS R01 CA129769NCI NIH HHS U54 CA132378NCI NIH HHS U54 CA137788NCRR NIH HHS M01 RR000096NCRR NIH HHS M01RR00096NCRR NIH HHS UL1RR02777NCRR NIH HHS UL1 RR029893NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NIA NIH HHS 1R01AG035137NIA NIH HHS 1RC2AG036502NIA NIH HHS 5R01AG012101NIA NIH HHS 5R01AG013616NIA NIH HHS 5R01AG022374NIA NIH HHS AG010491NIA NIH HHS AG019757NIA NIH HHS AG021547NIA NIH HHS AG02365NIA NIH HHS AG025688NIA NIH HHS AG027944NIA NIH HHS AG030653NIA NIH HHS AG041232NIA NIH HHS AG041718NIA NIH HHS AG05128NIA NIH HHS AG05144NIA NIH HHS AG07562NIA NIH HHS K01 AG030514NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG010491NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG03991NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028377NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG08051NIA NIH HHS P30 AG10133NIA NIH HHS P50 AG005128NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005144NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008671NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG016575NIA NIH HHS P50 AG016576NIA NIH HHS P50 AG016577NIA NIH HHS P50 AG016582NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG033514NIA NIH HHS R01 AG011380NIA NIH HHS R01 AG012101NIA NIH HHS R01 AG013616NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017173NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020688NIA NIH HHS R01 AG021136NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG022374NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG026390NIA NIH HHS R01 AG026916NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG031272NIA NIH HHS R01 AG031581NIA NIH HHS R01 AG033193NIA NIH HHS R01 AG035137NIA NIH HHS R01 AG041232NIA NIH HHS R01 AG041718NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG 042437NIA NIH HHS R01 AG042437NIA NIH HHS R01 AG042611NIA NIH HHS R01AG042611NIA NIH HHS R01AG11380NIA NIH HHS R01 AG15819NIA NIH HHS R01 AG17917NIA NIH HHS R01AG21136NIA NIH HHS R01 AG30146NIA NIH HHS R01AG31272NIA NIH HHS R01AG33193NIA NIH HHS R37 AG015473NIA NIH HHS RC2 AG036502NIA NIH HHS RC2 AG036528NIA NIH HHS RC2 AG036535NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG10483NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026390NIA NIH HHS U24 AG026395NIA NIH HHS U24 AG041689NIA NIH HHS U24 AG056270NIMH NIH HHS MH60451NIMH NIH HHS P50 MH060451NIMH NIH HHS R01 MH080295NINDS NIH HHS NS39764NINDS NIH HHS P50 NS039764NINDS NIH HHS R01 NS059873Wellcome Trust
6 · The paper itself

Abstract

introductionEbbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study.

methodsWe tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants.

resultsResults support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. DISCUSSION: We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

Indexed as

Epistasis, GeneticAllelesAlzheimer DiseaseApolipoprotein E4ClusterinFemaleGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyHumansMaleMembrane ProteinsRisk FactorsSialic Acid Binding Ig-like Lectin 3Apolipoprotein E4CD33 protein, humanCLU protein, humanClusterinMembrane ProteinsMS4A4E protein, humanSialic Acid Binding Ig-like Lectin 3ADGCADNIAlzheimer's diseaseCD33CLUEpistasisMeta-analysisMS4A4E

Identifiers

PMID26449541
PMCPMC4744542
OpenAlexW1961398302

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.