title: Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
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.
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Johanna
authors.identifier: http://orcid.org/0000-0002-8019-9683
authors.initials: J
authors.lastname: Jakobsdottir
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sven J
authors.identifier: http://orcid.org/0000-0003-1606-8643
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.|Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chouraki
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital Houston, Texas, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Li-Kroeger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shinya
authors.identifier: http://orcid.org/0000-0003-2172-8036
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Grove
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Naj
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Vronskaya
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jose L
authors.identifier: http://orcid.org/0000-0002-1727-306X
authors.initials: JL
authors.lastname: Salazar
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland, United States of America.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sims
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Seung-Hoan
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.|Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Claudia L
authors.identifier: http://orcid.org/0000-0002-1115-4430
authors.initials: CL
authors.lastname: Satizabal
authors.affiliation: Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.|Framingham Heart Study, Framingham, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Alexa
authors.initials: A
authors.lastname: Beiser
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus University Medical Center, CA Rotterdam, The Netherlands.|Departments of Radiology, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Garcia
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
authors.forename: Tibor V
authors.identifier: http://orcid.org/0000-0002-2383-699X
authors.initials: TV
authors.lastname: Varga
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.|Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Rolandsson
authors.affiliation: Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.|Research Unit, Skellefteå Hospital, Skellefteå, Sweden.
authors.forename: Jan-Håkon
authors.initials: JH
authors.lastname: Jansson
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Howard Hughes Medical Institute, Durham, North Carolina, United States of America.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United states of America.|Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus University Medical Center, CA Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Valur
authors.initials: V
authors.lastname: Emilsson
authors.affiliation: Institute 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.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Centre for Public Health, University of Iceland, Reykjavik, Iceland.
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United states of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.|Collaborative Health Studies Coordinating Center, Seattle, Washington, United States of America.
authors.forename: Annette L
authors.initials: AL
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authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, United States of America.
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authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
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authors.affiliation: Department of Pathology and Laboratory of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Pathology and Laboratory of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.|Department of Health Services, University of Washington, Seattle, Washington, United States of America.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
authors.forename: Bruce M
authors.initials: BM
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authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, United States of America.|Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital Houston, Texas, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland, United States of America.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007055:Iceland; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D051880:Receptors, Notch / Q000235:genetics*; D014335:Tropomyosin / Q000235:genetics*; D044465:White People
chemical_list: C000618215:Amx protein, Drosophila; D016564:Amyloid beta-Protein Precursor; C000612345:ApoE protein, human; D001057:Apolipoproteins E; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C431143:TM2D1 protein, human; D014335:Tropomyosin; C116431:src kinase associated phosphoprotein 2