ArticlePLoS genetics2016
Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Erratum issuedOpen access · goldAbstract read
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Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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34citing papers in PubMed
6.0field-weighted citation impact, top 3% of its field
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Who cites it
34 citing papers in PubMed, 60 citations in OpenAlex.
- Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.American journal of human genetics · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- Is the Relationship Between Cardiovascular Disease and Alzheimer's Disease Genetic? A Scoping Review.Genes · 2024Article
- A comparative study of structural variant calling in WGS from Alzheimer's disease families.Life science alliance · 2024Article
- Identification of Protein Biomarkers for DifferentiatingFoods (Basel, Switzerland) · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.Scientific reports · 2023Article
- Review
- The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.Human molecular genetics · 2022Article
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
- Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila.Methods in molecular biology (Clifton, N.J.) · 2022Article
- TM2D genes regulate Notch signaling and neuronal function in Drosophila.PLoS genetics · 2021Article
- Germline risk of clonal haematopoiesis.Nature reviews. Genetics · 2021Review
- The Application of Artificial Intelligence in the Genetic Study of Alzheimer's Disease.Aging and disease · 2020Review
- Post-Developmental Roles of Notch Signaling in the Nervous System.Biomolecules · 2020Review
- Whole-Genome Resequencing of TwentyBioMed research international · 2020Article
- The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases.Human molecular genetics · 2019Article
- In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila.Journal of visualized experiments : JoVE · 2019Article
- CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.Aging cell · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
55 authors at 20 institutions in 6 countries.
Johanna JakobsdottirIcelandic Heart Association, Kopavogur, Iceland.ORCID http://orcid.org/0000-0002-8019-9683
Sven J van der LeeDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID http://orcid.org/0000-0003-1606-8643
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Vincent ChourakiBoston University School of Medicine, Boston, Massachusetts, United States of America.
David Li-KroegerDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Shinya YamamotoDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.ORCID http://orcid.org/0000-0003-2172-8036
Megan L GroveSchool of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Adam NajDepartment of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Maria VronskayaInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
Jose L SalazarDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.ORCID http://orcid.org/0000-0002-1727-306X
Anita L DeStefanoFramingham Heart Study, Framingham, Massachusetts, United States of America.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Albert V SmithIcelandic Heart Association, Kopavogur, Iceland.
Najaf AminDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Rebecca SimsInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
Carla A Ibrahim-VerbaasDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Seung-Hoan ChoiFramingham Heart Study, Framingham, Massachusetts, United States of America.
Claudia L SatizabalBoston University School of Medicine, Boston, Massachusetts, United States of America.ORCID http://orcid.org/0000-0002-1115-4430
Oscar L LopezDepartment of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
Alexa BeiserBoston University School of Medicine, Boston, Massachusetts, United States of America.
M Arfan IkramDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Melissa E GarciaLaboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America.
Caroline HaywardMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Tibor V VargaDepartment of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.ORCID http://orcid.org/0000-0002-2383-699X
Samuli RipattiInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Paul W FranksDepartment of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
Göran HallmansDepartment of Biobank Research, Umeå University, Umeå, Sweden.
Olov RolandssonDepartment of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
Jan-Håkon JanssonDepartment of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
David J PorteousGeneration Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Veikko SalomaaNational Institute for Health and Welfare, Helsinki, Finland.
Gudny EiriksdottirIcelandic Heart Association, Kopavogur, Iceland.
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Hugo J BellenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Daniel LevyFramingham Heart Study, Framingham, Massachusetts, United States of America.
Andre G UitterlindenDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Valur EmilssonIcelandic Heart Association, Kopavogur, Iceland.
Jerome I RotterInstitute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Departments of Medicine and Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
Thor AspelundIcelandic Heart Association, Kopavogur, Iceland.
Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
Alzheimer’s Disease Genetic Consortium
Genetic and Environmental Risk in Alzheimer’s Disease consortium
Christopher J O'DonnellFramingham Heart Study, Framingham, Massachusetts, United States of America.
Annette L FitzpatrickDepartment of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Lenore J LaunerLaboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America.
Albert HofmanDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Li-San WangDepartment of Pathology and Laboratory of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Julie WilliamsInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
Gerard D SchellenbergDepartment of Pathology and Laboratory of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Eric BoerwinkleSchool of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Sudha SeshadriBoston University School of Medicine, Boston, Massachusetts, United States of America.
Joshua M ShulmanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Vilmundur GudnasonIcelandic Heart Association, Kopavogur, Iceland.
Cornelia M van DuijnDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Boston University · USErasmus MC · NLBaylor College of Medicine · USUniversity of Iceland · ISUniversity of Washington · USCardiff University · GBUniversity of Pennsylvania · USEdinburgh Cancer Research · GBIcelandic Heart Association · ISNational Institute on Aging · USUmeå University · SEFinnish Institute for Health and Welfare · FIGroup Health Cooperative · USHarvard University · USHoward Hughes Medical Institute · USLund University · SENational Institutes of Health · USSkellefteå Hospital · SEThe Lundquist Institute · USThe University of Texas Health Science Center at Houston · US
Funding
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MNational 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
$119.8MNATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8MAlzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MUCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4MUPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI XIE, SHARON XIANGWEN · 1991 to 2020
$35.1MThe 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
$31.4MUC Davis Alzheimer's Disease Core CenterP30AG010129 · NIA · UNIVERSITY OF CALIFORNIA DAVIS · PI DECARLI, CHARLES · 1991 to 2020
$28.3MBuilding on GWAS for NHLBI-disease: the CHARGE consortiumRC2HL102419 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2009 to 2010
$27.6MPRECURSORS OF STROKE INCIDENCE AND PROGNOSISR01NS017950 · NINDS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Hugo Javier Aparicio, Jose Rafael Romero · 1985 to 2026
$22.9MNRI Build-out: Advancing Translational Brain ResearchC06RR029965 · NCRR · BAYLOR COLLEGE OF MEDICINE · PI ZOGHBI, HUDA Y · 2010 to 2010
$14.9MChief Scientist Office CZD/16/6/4Medical Research Council G0300429Medical Research Council G0902227Medical Research Council MC_PC_U127561128Medical Research Council MR/K013041/1Medical Research Council MR/L010305/1Medical Research Council MR/L023784/1Medical Research Council MR/L023784/2Medical Research Council MR/L501517/1NCATS NIH HHS UL1 TR000124NCRR NIH HHS C06 RR029965NHGRI NIH HHS U54 HG003273NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL120393NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL130114NIA NIH HHS N01 AG012100NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS R01 AG033193NIA NIH HHS R01 AG050631NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG049505NIA NIH HHS U01 AG049506NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG056270NICHD NIH HHS U54 HD083092NIDA NIH HHS HHSN271201200022CNIDDK NIH HHS P30 DK063491NIGMS NIH HHS R25 GM056929NIGMS NIH HHS T32 GM008307NINDS NIH HHS R01 NS017950
Abstract
We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Indexed as
AgedAge of OnsetAllelesAlzheimer DiseaseAmyloid beta-Protein PrecursorAnimalsApolipoproteins EDrosophila melanogasterDrosophila ProteinsExomeFemaleGenome-Wide Association StudyGenomicsHumansIcelandIntracellular Signaling Peptides and ProteinsAmx protein, DrosophilaAmyloid beta-Protein PrecursorApoE protein, humanApolipoproteins EDrosophila ProteinsIntracellular Signaling Peptides and ProteinsMembrane ProteinsReceptors, Notchsrc kinase associated phosphoprotein 2TM2D1 protein, humanTropomyosin
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