Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
24336208
TITLE
Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.
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.
DATE PUBLISHED
2014 Jan 23
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2013/08/07
accepted 2013/10/31
aheadofprint 2013/12/11
entrez 2013/12/17 06:00
pubmed 2013/12/18 06:00
medline 2014/02/05 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Cruchaga C Cruchaga Carlos C 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Karch CM Karch Celeste M CM 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3].
Jin SC Jin Sheng Chih SC 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2].
Benitez BA Benitez Bruno A BA Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Cai Y Cai Yefei Y Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Guerreiro R Guerreiro Rita R 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Harari O Harari Oscar O Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Norton J Norton Joanne J Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Budde J Budde John J Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Bertelsen S Bertelsen Sarah S Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Jeng AT Jeng Amanda T AT Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Cooper B Cooper Breanna B Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Skorupa T Skorupa Tara T Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Carrell D Carrell David D Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Levitch D Levitch Denise D Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Hsu S Hsu Simon S Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Choi J Choi Jiyoon J Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Ryten M Ryten Mina M Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
UK Brain Expression Consortium
Hardy J Hardy John J Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Ryten M Ryten Mina M Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Trabzuni D Trabzuni Daniah D Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Weale ME Weale Michael E ME Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF UK.
Ramasamy A Ramasamy Adaikalavan A Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF UK.
Smith C Smith Colin C MRC Sudden Death Brain Bank Project, University of Edinburgh, South Bridge, Edinburgh EH8 9YL UK.
Sassi C Sassi Celeste C 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Bras J Bras Jose J Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Gibbs JR Gibbs J Raphael JR 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Hernandez DG Hernandez Dena G DG 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Lupton MK Lupton Michelle K MK 1] Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK [2] Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia.
Powell J Powell John J Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK.
Forabosco P Forabosco Paola P Istituto di Genetica delle Popolazioni - CNR, Trav. La Crucca, 3 - Reg. Baldinca - 07100 Li Punti, Sassari, Italy.
Ridge PG Ridge Perry G PG Department of Biology, Brigham Young University, Provo, Utah 84602, USA.
Corcoran CD Corcoran Christopher D CD 1] Department of Mathematics and Statistics, Utah State University, Logan, Utah 84322, USA [2] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA.
Tschanz JT Tschanz Joann T JT 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA.
Norton MC Norton Maria C MC 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA [3] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA.
Munger RG Munger Ronald G RG 1] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA [2] Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, Utah 84322, USA.
Schmutz C Schmutz Cameron C Department of Biology, Brigham Young University, Provo, Utah 84602, USA.
Leary M Leary Maegan M Department of Biology, Brigham Young University, Provo, Utah 84602, USA.
Demirci FY Demirci F Yesim FY Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
Bamne MN Bamne Mikhil N MN Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
Wang X Wang Xingbin X Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
Lopez OL Lopez Oscar L OL 1] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
Ganguli M Ganguli Mary M Department of Psychiatry, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
Medway C Medway Christopher C Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Turton J Turton James J Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Lord J Lord Jenny J Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Braae A Braae Anne A Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Barber I Barber Imelda I Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Brown K Brown Kristelle K Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Alzheimer’s Research UK Consortium
Passmore P Passmore Peter P Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
Craig D Craig David D Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
Johnston J Johnston Janet J Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
McGuinness B McGuinness Bernadette B Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
Todd S Todd Stephen S Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
Heun R Heun Reinhard R Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK.
Kölsch H Kölsch Heike H University of Bonn, Regina-Pacis-Weg 3, 53113 Bonn, Germany.
Kehoe PG Kehoe Patrick G PG University of Bristol, Tyndall Avenue, Bristol, City of Bristol BS8 1TH, UK.
Hooper NM Hooper Nigel M NM University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, UK.
Vardy ER Vardy Emma R L C ER University of Newcastle, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK.
Mann DM Mann David M DM University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, UK.
Pickering-Brown S Pickering-Brown Stuart S University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, UK.
Brown K Brown Kristelle K Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Kalsheker N Kalsheker Noor N Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Lowe J Lowe James J Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Morgan K Morgan Kevin K Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
David Smith A David Smith A A University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK.
Wilcock G Wilcock Gordon G University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK.
Warden D Warden Donald D University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK.
Holmes C Holmes Clive C University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK.
Pastor P Pastor Pau P 1] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pío XII, 55. 31008 Pamplona, Navarra, Spain [2] Department of Neurology, Clínica Universidad de Navarra, School of Medicine, University of Navarra Avenida Pío XII, 36. 31008 Pamplona, Spain [3] CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
Lorenzo-Betancor O Lorenzo-Betancor Oswaldo O Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pío XII, 55. 31008 Pamplona, Navarra, Spain.
Brkanac Z Brkanac Zoran Z University of Washington, 325 Ninth Avenue, Seattle, Washington 98104-2499, USA.
Scott E Scott Erick E The Scripps Research Institute, La Jolla, California 3344 North Torrey Pines Court, La Jolla, California 92037, USA.
Topol E Topol Eric E The Scripps Research Institute, La Jolla, California 3344 North Torrey Pines Court, La Jolla, California 92037, USA.
Morgan K Morgan Kevin K Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Rogaeva E Rogaeva Ekaterina E Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
Singleton AB Singleton Andrew B AB Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Hardy J Hardy John J Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Kamboh MI Kamboh M Ilyas MI 1] Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [3] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
St George-Hyslop P St George-Hyslop Peter P 1] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada [2] Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
Cairns N Cairns Nigel N 1] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Morris JC Morris John C JC 1] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Kauwe JS Kauwe John S K JS Department of Biology, Brigham Young University, Provo, Utah 84602, USA.
Goate AM Goate Alison M AM 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [4] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [5] Department of Genetics, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
INVESTIGATORS
JOURNAL
VOLUME: 505
ISSUE: 7484
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2014
MONTH: Jan
DAY: 23
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
081864 Wellcome Trust United Kingdom
089698 Wellcome Trust United Kingdom
089703 Wellcome Trust United Kingdom
100140 Wellcome Trust United Kingdom
1R01AG041797 NIA NIH HHS United States
5U24AG026395 NIA NIH HHS United States
AG005133 NIA NIH HHS United States
AG023652 NIA NIH HHS United States
AG030653 NIA NIH HHS United States
AG041718 NIA NIH HHS United States
AG07562 NIA NIH HHS United States
G0802189 Medical Research Council United Kingdom
G0802462 Medical Research Council United Kingdom
G0901254 Medical Research Council United Kingdom
G1100695 Medical Research Council United Kingdom
K01 AG046374 NIA NIH HHS United States
MC_G1000734 Medical Research Council United Kingdom
MC_G1000735 Medical Research Council United Kingdom
NIH P50 AG05681 NIA NIH HHS United States
NIH R01039700 PHS HHS United States
P01 AG003991 NIA NIH HHS United States
P01 AG026276 NIA NIH HHS United States
P01 AG026276 NIA NIH HHS United States
P01 AG03991 NIA NIH HHS United States
P30 NS069329 NINDS NIH HHS United States
P30-NS069329 NINDS NIH HHS United States
P50 AG005133 NIA NIH HHS United States
P50 AG005681 NIA NIH HHS United States
R01 AG011380 NIA NIH HHS United States
R01 AG030653 NIA NIH HHS United States
R01 AG035083 NIA NIH HHS United States
R01 AG039700 NIA NIH HHS United States
R01 AG041718 NIA NIH HHS United States
R01 AG041797 NIA NIH HHS United States
R01 AG042611 NIA NIH HHS United States
R01 AG044546 NIA NIH HHS United States
R01-AG035083 NIA NIH HHS United States
R01-AG042611 NIA NIH HHS United States
R01-AG044546 NIA NIH HHS United States
R01-AG11380 NIA NIH HHS United States
R01-AG18712 NIA NIH HHS United States
R01-AG21136 NIA NIH HHS United States
R01AG21136 NIA NIH HHS United States
R25 DA027995 NIDA NIH HHS United States
U24 AG021886 NIA NIH HHS United States
U24 AG026395 NIA NIH HHS United States
U24AG21886 NIA NIH HHS United States
WT089698 Wellcome Trust United Kingdom
ZIA AG000950-11 Intramural NIH HHS United States
ZO1 AG000950-10 NIA NIH HHS United States
ZO1AG000950-11 NIA NIH HHS United States
Canadian Institutes of Health Research Canada
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
African Americans genetics
Age of Onset genetics
Aged genetics
Aged, 80 and over genetics
Alzheimer Disease metabolism
Amyloid beta-Peptides metabolism
Amyloid beta-Protein Precursor metabolism
Brain metabolism
Case-Control Studies metabolism
Europe ethnology
Exome genetics
Female genetics
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Humans genetics
Male genetics
Peptide Fragments metabolism
Phospholipase D metabolism
Protein Processing, Post-Translational genetics
Proteolysis genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 APP protein, human
0 Amyloid beta-Peptides
0 Amyloid beta-Protein Precursor
0 Peptide Fragments
0 amyloid beta-protein (1-40)
0 amyloid beta-protein (1-42)
EC 3.1.4.4 Phospholipase D
EC 3.1.4.4 phospholipase D3, human
OTHER ID's
OTHERID SOURCE
NIHMS578392 NLM
PMC4050701 NLM