Evidence map›Paper›PMID 24336208›Full record

ArticleNature2014

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Carlos Cruchaga, Celeste M Karch, Sheng Chih Jin, Bruno A Benitez, Yefei Cai, Rita Guerreiro, Oscar Harari, Joanne Norton, John Budde, Sarah Bertelsen and 49 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 267 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
267citing papers in PubMed, 5 pooled it
39.4field-weighted citation impact, top 1% 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

267 citing papers in PubMed, 5 syntheses or guidelines pooled it, 472 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2016
    Pooled it
  6. Article
  7. Article
  8. Review
  9. Integrative genomic and functional analyses reveal NINL as a modulator of tau aggregation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
  10. Review
  11. Review
  12. Article
  13. Article
  14. Article
  15. Review
  16. Review
  17. Article
  18. LMTK2 and CRB1 are two novel risk genes for Alzheimer's disease in Han Chinese.The journal of prevention of Alzheimer's disease · 2025
    Article
  19. Review
  20. Article

207 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

59 authors at 20 institutions in 7 countries.

Carlos CruchagaDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Celeste M Karch *Department of Psychiatry, Washington University, St. Louis, MO, USA.
Sheng Chih Jin *Department of Psychiatry, Washington University, St. Louis, MO, USA.
Bruno A BenitezDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Yefei CaiDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Rita GuerreiroDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Oscar HarariDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Joanne NortonDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
John BuddeDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Sarah BertelsenDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Amanda T JengDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Breanna CooperDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Tara SkorupaDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
David CarrellDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Denise LevitchDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Simon HsuDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Jiyoon ChoiDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Mina RytenDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Celeste SassiDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Jose BrasDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Raphael J GibbsDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Dena G HernandezDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Michelle K LuptonInstitute of Psychiatry, King's College London, London, UK.
John PowellInstitute of Psychiatry, King's College London, London, UK.
Paola ForaboscoIstituto di Genetica delle Popolazioni - CNR, Sassari, Italy.
Perry G RidgeDepartment of Biology, Brigham Young University, Provo, UT, 84602.
Christopher D CorcoranDepartment of Mathematics and Statistics, Utah State University, Logan, UT.
JoAnn T TschanzCenter for Epidemiologic Studies, Utah State University, Logan, UT.
Maria C NortonCenter for Epidemiologic Studies, Utah State University, Logan, UT.
Ronald G MungerDepartment of Family Consumer and Human Development, Utah State University, Logan, UT.
Cameron SchmutzDepartment of Biology, Brigham Young University, Provo, UT, 84602.
Maegan LearyDepartment of Biology, Brigham Young University, Provo, UT, 84602.
F Yesim DemirciDepartment of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Mikhil N BamneDepartment of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Xingbin WangDepartment of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Oscar L LopezAlzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.
Mary GanguliDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
Christopher MedwayHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
James TurtonHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Jenny LordHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Anne BraaeHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Imelda BarberHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Kristelle BrownHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Alzheimer's Research UK (ARUK) Consortium
Pau PastorNeurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Oswaldo Lorenzo-BetancorNeurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Zoran BrkanacUniversity of Washington. Seattle, WA.
Erick ScottThe Scripps Research Institute, La Jolla, CA, US.
Eric TopolThe Scripps Research Institute, La Jolla, CA, US.
Kevin MorganHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Ekaterina RogaevaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto.
Andy SingletonLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
John HardyDepartment of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
M Ilyas KambohAlzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.
Peter St George-HyslopTanz Centre for Research in Neurodegenerative Diseases, University of Toronto.
Nigel CairnsHope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
John C MorrisPathology and Immunology, Washington University, St. Louis, MO, USA.
John S K KauweDepartment of Biology, Brigham Young University, Provo, UT, 84602.
Alison M GoateDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Washington University in St. Louis · USQueen's Medical Centre · GBUniversity of Pittsburgh · USQueen's University Belfast · GBUniversity of Nottingham · GBBrigham Young University · USNational Hospital for Neurology and Neurosurgery · GBUniversity of Oxford · GBUtah State University · USKing's College London · GBNational Institutes of Health · USNational Institute on Aging · USScripps Research Institute · USUniversity College London · GBUniversity of Manchester · GBCentro de Investigación Biomédica en Red · ESIstituto di Genetica Molecolare · ITNewcastle University · GBOccupational Cancer Research Centre · CAQIMR Berghofer Medical Research Institute · AU

Funding

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
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI JOHN MORRIS · 1985 to 2026
$69.5M
WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1M
The natural history of AB accumulation in preclinical ADP01AG026276 · NIA · WASHINGTON UNIVERSITY · PI SCHINDLER, SUZANNE ELIZABETH · 2005 to 2025
$49.5M
TREATMENT OF DEPRESSION IN ALZHEIMER'S DISEASEP50AG005133 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI LINGLER, JENNIFER HAGERTY · 1985 to 2019
$43.0M
The National Institute on Aging (NIA) Late Onset of Alzheimer's Disease (LOAD) Family-Based Study (FBS)U24AG056270 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Gary Wayne Beecham, TATIANA M. FOROUD · 2017 to 2026
$31.4M
EPIDEMIOLOGY OF DEMENTIA IN CACHE COUNTY, UTAHR01AG011380 · NIA · JOHNS HOPKINS UNIVERSITY · PI WELSH-BOHMER, KATHLEEN ANNE · 1994 to 2009
$12.2M
Genetic Consortium for Late Onset Alzheimer's DiseaseU24AG026395 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MAYEUX, RICHARD P · 2005 to 2009
$10.1M
Search for the Alzheimers GenesR01AG030653 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI KAMBOH, M. ILYAS · 2009 to 2019
$7.7M
Genetic Analysis Of Alzheimer s DiseaseZIAAG000950 · NIA · NATIONAL INSTITUTE ON AGING · PI SINGLETON, ANDREW · 2009 to 2019
$6.9M
Progression of Dementia: A Population StudyR01AG021136 · NIA · UTAH STATE UNIVERSITY · PI LYKETSOS, CONSTANTINE G, TSCHANZ, JOANN T · 2002 to 2010
$6.0M
RESEARCH EDUCATION PROGRAM ON COMPUTATIONAL AND STATISTICAL TOOL DEVELOPMENT FOR ADDICTION GENETICSR25DA027995 · NIDA · WASHINGTON UNIVERSITY · PI MADDEN, PAMELA ANN, RICE, JOHN P. · 2009 to 2019
$4.3M
CIHRIntramural NIH HHS Z01 AG000950Intramural NIH HHS ZIA AG000950Medical Research Council G0802189Medical Research Council G0802462Medical Research Council G0901254Medical Research Council G1100695Medical Research Council MC_G1000734Medical Research Council MC_G1000735Medical Research Council MR/L016400/1NIA NIH HHS 1R01AG041797NIA NIH HHS 5U24AG026395NIA NIH HHS AG005133NIA NIH HHS AG023652NIA NIH HHS AG030653NIA NIH HHS AG041718NIA NIH HHS AG07562NIA NIH HHS K01 AG046374NIA NIH HHS NIH P50 AG05681NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG026276NIA NIH HHS P01 AG03991NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005681NIA NIH HHS R01 AG011380NIA NIH HHS R01 AG018712NIA NIH HHS R01 AG021136NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG035083NIA NIH HHS R01-AG035083NIA NIH HHS R01 AG039700NIA NIH HHS R01 AG041718NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG042611NIA NIH HHS R01-AG042611NIA NIH HHS R01 AG044546NIA NIH HHS R01-AG044546NIA NIH HHS R01-AG11380NIA NIH HHS R01-AG18712NIA NIH HHS R01-AG21136NIA NIH HHS R01AG21136NIA NIH HHS RF1 AG044546NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026395NIA NIH HHS U24 AG056270NIA NIH HHS U24AG21886NIA NIH HHS ZO1 AG000950-10NIA NIH HHS ZO1AG000950-11NIDA NIH HHS R25 DA027995NINDS NIH HHS P30 NS069329NINDS NIH HHS P30-NS069329PHS HHS NIH R01039700Wellcome Trust 081864Wellcome Trust 089698Wellcome Trust 089703Wellcome Trust 100140
6 · The paper itself

Abstract

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Indexed as

AgedAged, 80 and overAge of OnsetAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorBlack or African AmericanBrainCase-Control StudiesEuropeExodeoxyribonucleasesExomeFemaleGenetic Predisposition to DiseaseGenetic VariationHumansAmyloid beta-Peptidesamyloid beta-protein (1-40)amyloid beta-protein (1-42)Amyloid beta-Protein PrecursorAPP protein, humanExodeoxyribonucleasesPeptide FragmentsPhospholipase DPLD3 protein, human

Identifiers

PMID24336208
PMCPMC4050701
OpenAlexW2099248872

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Read underepoch 390

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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.