Evidence map›Paper›PMID 25961151›Full record

ArticleJAMA neurology2015

Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.

Paul L Auer, Mike Nalls, James F Meschia, Bradford B Worrall, W T Longstreth, Sudha Seshadri, Charles Kooperberg, Kathleen M Burger, Christopher S Carlson, Cara L Carty and 19 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JAMA neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed, 1 pooled it
5.3field-weighted citation impact, top 4% 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

36 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.

  1. Pooled it
  2. AnGenes · 2026
    Article
  3. Article
  4. Review
  5. Article
  6. Review
  7. Article
  8. Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. PDE4DIP in health and diseases.Cellular signalling · 2022
    Review
  16. Article
  17. Article
  18. Article
  19. Article
  20. Frontiers in cardiovascular medicine · 2021
    Article
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

29 authors at 12 institutions in 2 countries.

Paul L AuerJoseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee2Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Mike NallsLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
James F MeschiaDepartment of Neurology, Mayo Clinic, Jacksonville, Florida.
Bradford B WorrallDepartment of Neurology, University of Virginia, Charlottesville.
W T LongstrethDepartment of Neurology, University of Washington, Seattle.
Sudha SeshadriDepartment of Neurology, Boston University School of Medicine, Boston, Massachusetts.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Kathleen M BurgerDepartment of Neurology, George Washington University Hospital, Washington, DC.
Christopher S CarlsonDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Cara L CartyDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Wei-Min ChenCenter for Public Health Genomics, University of Virginia, Charlottesville.
L Adrienne CupplesDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Anita L DeStefanoDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Myriam FornageInstitute for Molecular Medicine, University of Texas Health Science Center, Houston.
John HardyDepartment of Neuroscience, Reta Lila Weston Institute, University College London, London, England.
Li HsuDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Rebecca D JacksonDepartment of Internal Medicine, The Ohio State University, Columbus.
Gail P JarvikDepartment of Medicine, University of Washington, Seattle.
Daniel S KimDepartment of Genome Sciences, University of Washington, Seattle.
Kamakshi LakshminarayanDepartment of Neurology, University of Minnesota, Minneapolis.
Leslie A LangeDepartment of Genetics, University of North Carolina, Chapel Hill.
Ani ManichaikulCenter for Public Health Genomics, University of Virginia, Charlottesville.
Aaron R QuinlanCenter for Public Health Genomics, University of Virginia, Charlottesville.
Andrew B SingletonLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Timothy A ThorntonDepartment of Biostatistics, University of Washington, Seattle.
Deborah A NickersonDepartment of Genome Sciences, University of Washington, Seattle.
Ulrike PetersDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville.
National Heart, Lung, and Blood Institute Exome Sequencing Project
Fred Hutch Cancer Center · USUniversity of Virginia · USUniversity of Washington · USBoston University · USNational Institutes of Health · USGeorge Washington University Hospital · USJacksonville College · USThe Ohio State University · USThe University of Texas Health Science Center at Houston · USUniversity College London · GBUniversity of Minnesota · USUniversity of North Carolina at Chapel Hill · US

Funding

Translational Bioimaging Core Shared ResourceP30CA015704 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Eric Collisson · 1985 to 2026
$296.4M
Transform Dissemination and Implementation Science in CTSA ProgramsUL1TR002319 · NCATS · UNIVERSITY OF WASHINGTON · PI John K. Amory · 2017 to 2026
$100.0M
Genetic Epidemiology of COPDU01HL089897 · NHLBI · NATIONAL JEWISH HEALTH · PI CRAPO, JAMES D · 2007 to 2021
$56.9M
INSTITUTE FOR TRANSLATIONAL HEALTH SCIENCE (UL1): BPCAUL1RR025014 · NCRR · UNIVERSITY OF WASHINGTON · PI DISIS, MARY L. · 2007 to 2011
$51.5M
Institute of Translational Health SciencesUL1TR000423 · NCATS · UNIVERSITY OF WASHINGTON · PI DISIS, MARY L. · 2012 to 2016
$49.4M
WORKER PROTECTION AGAINST AIRBORNE INFLUENZA - A PILOT STUDYM01RR007122 · NCRR · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI KOCH, KENNETH L · 1992 to 2010
$35.2M
UC Davis Alzheimer's Disease Core CenterP30AG010129 · NIA · UNIVERSITY OF CALIFORNIA DAVIS · PI DECARLI, CHARLES · 1991 to 2020
$28.3M
PRECURSORS OF STROKE INCIDENCE AND PROGNOSISR01NS017950 · NINDS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Hugo Javier Aparicio, Jose Rafael Romero · 1985 to 2026
$22.9M
Genetic Epidemiology of COPDU01HL089856 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI SILVERMAN, EDWIN K · 2007 to 2021
$20.7M
SCLERODERMA-ASSOCIATED PAHP50HL084946 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI HASSOUN, PAUL M. · 2007 to 2011
$20.6M
EPIDEMIOLOGY OF DEMENTIA IN THE FRAMINGHAM STUDYR01AG008122 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI AU, RHODA, SESHADRI, SUDHA · 1989 to 2015
$14.4M
Northwest Genomics CenterRC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2009 to 2009
$11.0M
Intramural NIH HHS Z01 AG000954NCATS NIH HHS UL1 TR000423NCATS NIH HHS UL1 TR002319NCI NIH HHS P30 CA015704NCRR NIH HHS M01 RR007122NCRR NIH HHS M01-RR07122NCRR NIH HHS UL1 RR025014NCRR NIH HHS UL1-RR025014NHGRI NIH HHS 5R00-HG004316NHGRI NIH HHS R00 HG004316NHGRI NIH HHS R01-HG004738NHGRI NIH HHS U01 HG004738NHLBI NIH HHS F32 HL083714NHLBI NIH HHS F32-HL083714NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100001INHLBI NIH HHS HHSN268201100002INHLBI NIH HHS HHSN268201100003INHLBI NIH HHS HHSN268201100004INHLBI NIH HHS HHSN268201100046CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HL077916NHLBI NIH HHS HL-69197NHLBI NIH HHS HL-76285NHLBI NIH HHS HR-46002NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC048047NHLBI NIH HHS N01 HC048048NHLBI NIH HHS N01 HC048049NHLBI NIH HHS N01 HC048050NHLBI NIH HHS N01 HC055015NHLBI NIH HHS N01 HC055016NHLBI NIH HHS N01 HC055018NHLBI NIH HHS N01 HC055019NHLBI NIH HHS N01 HC055020NHLBI NIH HHS N01 HC055021NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01 HC095095NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095169NHLBI NIH HHS N01 HC095170NHLBI NIH HHS N01 HC095171NHLBI NIH HHS N01 HC095172NHLBI NIH HHS N01-HC-25195NHLBI NIH HHS N01-HC48047NHLBI NIH HHS N01-HC48048NHLBI NIH HHS N01-HC48049NHLBI NIH HHS N01-HC48050NHLBI NIH HHS N01 HC-55015NHLBI NIH HHS N01 HC-55016NHLBI NIH HHS N01HC-55017NHLBI NIH HHS N01 HC-55019NHLBI NIH HHS N01 HC-55020NHLBI NIH HHS N01 HC-55021NHLBI NIH HHS N01-HC95095NHLBI NIH HHS N01-HC-95159NHLBI NIH HHS N01-HC-95160NHLBI NIH HHS N01-HC-95161NHLBI NIH HHS N01-HC-95162NHLBI NIH HHS N01-HC-95163NHLBI NIH HHS N01-HC-95164NHLBI NIH HHS N01-HC-95165NHLBI NIH HHS N01-HC-95166NHLBI NIH HHS N01-HC-95167NHLBI NIH HHS N01-HC-95168NHLBI NIH HHS N01-HC-95169NHLBI NIH HHS N01 HC-95170NHLBI NIH HHS N01 HC-95171NHLBI NIH HHS N01 HC-95172NHLBI NIH HHS N01 HR046002NHLBI NIH HHS P50 HL084946NHLBI NIH HHS P50-HL084946NHLBI NIH HHS R01 HL068890NHLBI NIH HHS R01-HL068890NHLBI NIH HHS R01 HL076285NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01HL087652NHLBI NIH HHS R01 HL095396NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01HL105756NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01HL120393NHLBI NIH HHS R02-HL095396NHLBI NIH HHS R21 HL077916NHLBI NIH HHS RC2-HL066583NHLBI NIH HHS RC2 HL101651NHLBI NIH HHS RC2-HL101651NHLBI NIH HHS RC2 HL101779NHLBI NIH HHS RC2-HL101779NHLBI NIH HHS RC2 HL-102923NHLBI NIH HHS RC2 HL102923NHLBI NIH HHS RC2 HL-102924NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS RC2-HL102924NHLBI NIH HHS RC2 HL-102925NHLBI NIH HHS RC2 HL102925NHLBI NIH HHS RC2 HL-102926NHLBI NIH HHS RC2 HL102926NHLBI NIH HHS RC2 HL-103010NHLBI NIH HHS RC2 HL103010NHLBI NIH HHS U01 HL066583NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01HL080295NHLBI NIH HHS U01 HL089856NHLBI NIH HHS U01-HL089856NHLBI NIH HHS U01 HL089897NHLBI NIH HHS U01-HL089897NIAMS NIH HHS K23 AR052742NIAMS NIH HHS K23-AR52742NIA NIH HHS AG033193NIA NIH HHS AG08122NIA NIH HHS HHSN271201100004CNIA NIH HHS P30 AG010129NIA NIH HHS R01 AG008122NIA NIH HHS R01 AG023629NIA NIH HHS R01AG023629NIA NIH HHS R01 AG033193NIA NIH HHS U01 AG049505NIA NIH HHS Z01-AG000954-7NIH HHS S10 OD020069NINDS NIH HHS NS17950NINDS NIH HHS R01 NS017950NINDS NIH HHS R01 NS039987NINDS NIH HHS R01 NS042733NINDS NIH HHS R01-NS39987NINDS NIH HHS R01-NS42733PHS HHS 024156WHI NIH HHS HHSN268201100001CWHI NIH HHS HHSN268201100002CWHI NIH HHS HHSN268201100003CWHI NIH HHS HHSN268201100004C
6 · The paper itself

Abstract

importanceStroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

objectiveTo investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. DESIGN, SETTING, AND

participantsThe National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

resultsWe identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

Indexed as

National Heart, Lung, and Blood Institute (U.S.)Adaptor Proteins, Signal TransducingAgedBrain IschemiaCytoskeletal ProteinsExomeFemaleGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyHumansMaleMiddle AgedMuscle ProteinsNuclear ProteinsOpen Reading FramesACOT4 protein, humanAdaptor Proteins, Signal TransducingCytoskeletal ProteinsMuscle ProteinsNuclear ProteinsPalmitoyl-CoA HydrolasePDE4DIP protein, human

Identifiers

PMID25961151
PMCPMC4673986
OpenAlexW2139892622

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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.