Evidence map›Paper›PMID 25706306›Full record

ArticleJAMA neurology2015

A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.

Jason A Chen, Qing Wang, Jeremy Davis-Turak, Yun Li, Anna M Karydas, Sandy C Hsu, Renee L Sears, Doxa Chatzopoulou, Alden Y Huang, Kevin J Wojta and 25 more

Open access · greenAbstract 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 30 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed, 2 pooled it
3.4field-weighted citation impact, top 8% 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

30 citing papers in PubMed, 2 syntheses or guidelines pooled it, 44 citations in OpenAlex.

  1. Pooled it
  2. TREM2 variants and risk of Alzheimer's disease: a meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2015
    Pooled it
  3. Article
  4. Plasma membrane repair defect in Alzheimer's disease neurons is driven by the reduced dysferlin expression.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024
    Article
  5. Article
  6. The ABC's of Alzheimer risk gene ABCA7.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024
    Review
  7. Review
  8. Otoferlin as a multirole CaFrontiers in cellular neuroscience · 2023
    Review
  9. The influence of 17q21.31 andFrontiers in aging neuroscience · 2022
    Review
  10. Article
  11. HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review.International journal of molecular sciences · 2021
    Review
  12. Review
  13. Article
  14. Review
  15. Article
  16. Review
  17. Article
  18. Review
  19. Review
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

35 authors at 13 institutions in 1 country.

Jason A ChenSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Qing WangSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Jeremy Davis-TurakSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Yun LiSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Anna M KarydasMemory and Aging Center, University of California, San Francisco.
Sandy C HsuSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Renee L SearsSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Doxa ChatzopoulouSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Alden Y HuangSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Kevin J WojtaSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Eric KleinSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Jason LeeSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Duane L BeeklyNational Alzheimer's Coordinating Center, University of Washington, Seattle.
Adam BoxerMemory and Aging Center, University of California, San Francisco.
Kelley M FaberDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
Claudia M HaaseDepartment of Psychology, School of Education and Social Policy, Northwestern University, Evanston, Illinois.
Josh MillerDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.
Wayne W PoonInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine.
Ami RosenDepartment of Neurology, Emory University, Atlanta, Georgia.
Howard RosenMemory and Aging Center, University of California, San Francisco.
Anna SapozhnikovaDepartment of Psychology, University of California, Berkeley.
Jill ShapiraDepartment of Neurology, University of California, Los Angeles.
Arousiak VarpetianDepartment of Neurology, University of Southern California, Los Angeles.
Tatiana M ForoudDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
Robert W LevensonDepartment of Psychology, University of California, Berkeley.
Allan I LeveyDepartment of Neurology, Emory University, Atlanta, Georgia.
Walter A KukullNational Alzheimer's Coordinating Center, University of Washington, Seattle.
Mario F MendezDepartment of Neurology, University of California, Los Angeles.
John RingmanDepartment of Neurology, University of California, Los Angeles12Mary S. Easton Center for Alzheimer's Disease Research at UCLA, University of California, Los Angeles.
Helena ChuiDepartment of Neurology, University of Southern California, Los Angeles.
Carl CotmanInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine.
Charles DeCarliDepartment of Neurology, University of California, Davis.
Bruce L MillerMemory and Aging Center, University of California, San Francisco.
Daniel H GeschwindSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
Giovanni CoppolaSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
University of California, Los Angeles · USUniversity Memory and Aging Center · USEmory University · USIndiana University – Purdue University Indianapolis · USUniversity of California, Berkeley · USUniversity of California, Irvine · USUniversity of Southern California · USUniversity of Washington · USFoundation for Psychocultural Research · USNorthwestern University · USRutgers, The State University of New Jersey · USUniversity of California, Davis · USUniversity of California, San Francisco · US

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
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
VASCULAR RISK AND COGNITIVE STATUS IN A LATINO POPULATIONP50AG005142 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TOGA, ARTHUR W · 1985 to 2019
$41.0M
UC Irvine Alzheimer's Disease Research Center Induced Pluripotent Stem Cell CoreP50AG016573 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI LAFERLA, FRANK M · 2000 to 2019
$37.0M
University of California Health Participation in the National COVID Cohort Collaborative (N3C)UL1TR001414 · NCATS · UNIVERSITY OF CALIFORNIA-IRVINE · PI COOPER, DAN M, VILAIN, ERIC J. · 2015 to 2023
$35.1M
UC Davis Alzheimer's Disease Core CenterP30AG010129 · NIA · UNIVERSITY OF CALIFORNIA DAVIS · PI DECARLI, CHARLES · 1991 to 2020
$28.3M
Quality Assurance and Quality Control Project Management: Improving Submissions and Study Conduct in the Human Subjects Research Prior Approval ProcessUL1TR002529 · NCATS · INDIANA UNIVERSITY INDIANAPOLIS · PI MOE, SHARON M, WIEHE, SARAH ELIZABETH · 2018 to 2022
$27.2M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HUANG, YADONG · 2004 to 2018
$27.1M
UCLA ALZHEIMERS DISEASE RESEARCH CENTERP50AG016570 · NIA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CUMMINGS, JEFFREY L. · 1999 to 2014
$25.9M
The Emory Alzheimer's Disease CenterP50AG025688 · NIA · EMORY UNIVERSITY · PI WALKER, LARY C · 2005 to 2019
$25.7M
TISSUE REPOSITORY COREP01AG000538 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI POON, WAYNE W · 1985 to 2018
$24.8M
NCATS NIH HHS UL1 TR001108NCATS NIH HHS UL1 TR001414NIA NIH HHS P01 AG000538NIA NIH HHS P01 AG019724NIA NIH HHS P0I AG000538NIA NIH HHS P30 AG010129NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG05142NIA NIH HHS P50 AG16570NIA NIH HHS R01 AG026938NIA NIH HHS R01 AG032306NIA NIH HHS R01 AG038791NIA NIH HHS R01 AG041762NIA NIH HHS R01 AG042292NIA NIH HHS R01 AG26938NIA NIH HHS RC1 AG035610NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG016979NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG21886NIMH NIH HHS R01 MH097268NINDS NIH HHS F31 NS084556NINDS NIH HHS P30 NS062691NINDS NIH HHS U54 NS092089
6 · The paper itself

Abstract

importancePrevious studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.

objectiveTo identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND

participantsWe used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES: Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.

resultsGenetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE: Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

Indexed as

ExomeGenetic Predisposition to DiseaseAdultAgedAged, 80 and overAlzheimer DiseaseFemaleFrontotemporal DementiaGenetic TestingGenetic VariationGenome-Wide Association StudyGenotypeHumansMaleMicroarray AnalysisMiddle Aged

Identifiers

PMID25706306
PMCPMC4397175
OpenAlexW2018030093

What OpenQuestion holds

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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.