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.
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
authors: Carlos
authors: C
authors: Cruchaga
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
authors: Celeste M
authors: CM
authors: Karch
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Sheng Chih
authors: SC
authors: Jin
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Bruno A
authors: BA
authors: Benitez
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Yefei
authors: Y
authors: Cai
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Rita
authors: R
authors: Guerreiro
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Oscar
authors: O
authors: Harari
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Joanne
authors: J
authors: Norton
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: John
authors: J
authors: Budde
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Sarah
authors: S
authors: Bertelsen
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Amanda T
authors: AT
authors: Jeng
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Breanna
authors: B
authors: Cooper
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Tara
authors: T
authors: Skorupa
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: David
authors: D
authors: Carrell
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Denise
authors: D
authors: Levitch
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Simon
authors: S
authors: Hsu
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors: Jiyoon
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authors: Choi
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.|on behalf of UKBEC (UK Brain Expression Consortium).
authors: Mina
authors: M
authors: Ryten
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Celeste
authors: C
authors: Sassi
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors: Jose
authors: J
authors: Bras
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Raphael J
authors: RJ
authors: Gibbs
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Dena G
authors: DG
authors: Hernandez
authors: Institute of Psychiatry, King's College London, London, UK.|Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Michelle K
authors: MK
authors: Lupton
authors: Institute of Psychiatry, King's College London, London, UK.
authors: John
authors: J
authors: Powell
authors: Istituto di Genetica delle Popolazioni - CNR, Sassari, Italy.
authors: Paola
authors: P
authors: Forabosco
authors: Department of Biology, Brigham Young University, Provo, UT, 84602.
authors: Perry G
authors: PG
authors: Ridge
authors: Department of Mathematics and Statistics, Utah State University, Logan, UT.|Center for Epidemiologic Studies, Utah State University, Logan, UT.
authors: Christopher D
authors: CD
authors: Corcoran
authors: Center for Epidemiologic Studies, Utah State University, Logan, UT.|Department of Psychology, Utah State University, Logan, UT.
authors: JoAnn T
authors: JT
authors: Tschanz
authors: Center for Epidemiologic Studies, Utah State University, Logan, UT.|Department of Psychology, Utah State University, Logan, UT.|Department of Family Consumer and Human Development, Utah State University, Logan, UT.
authors: Maria C
authors: MC
authors: Norton
authors: Department of Family Consumer and Human Development, Utah State University, Logan, UT.|Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT.
authors: Ronald G
authors: RG
authors: Munger
authors: Department of Biology, Brigham Young University, Provo, UT, 84602.
authors: Cameron
authors: C
authors: Schmutz
authors: Department of Biology, Brigham Young University, Provo, UT, 84602.
authors: Maegan
authors: M
authors: Leary
authors: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
authors: F Yesim
authors: FY
authors: Demirci
authors: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
authors: Mikhil N
authors: MN
authors: Bamne
authors: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
authors: Xingbin
authors: X
authors: Wang
authors: Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.|Department of Neurology, University of Pittsburgh, Pittsburgh, PA.
authors: Oscar L
authors: OL
authors: Lopez
authors: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
authors: Mary
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authors: Ganguli
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Christopher
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authors: Medway
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: James
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authors: Turton
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Jenny
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authors: Lord
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Anne
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authors: Braae
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Imelda
authors: I
authors: Barber
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Kristelle
authors: K
authors: Brown
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.|Department of Neurology, Clínica Universidad de Navarra, School of Medicine, University of Navarra, Pamplona, Spain.|CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
authors: Pau
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authors: Pastor
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: Oswaldo
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authors: Lorenzo-Betancor
authors: University of Washington. Seattle, WA.
authors: Zoran
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authors: Brkanac
authors: The Scripps Research Institute, La Jolla, CA, US.
authors: Erick
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authors: The Scripps Research Institute, La Jolla, CA, US.
authors: Eric
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authors: Topol
authors: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
authors: Kevin
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authors: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto.
authors: Ekaterina
authors: E
authors: Rogaeva
authors: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Andy
authors: A
authors: Singleton
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors: John
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authors: Hardy
authors: Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.|Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.|Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
authors: M Ilyas
authors: MI
authors: Kamboh
authors: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto.|Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge.
authors: Peter St
authors: PS
authors: George-Hyslop
authors: Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.|Pathology and Immunology, Washington University, St. Louis, MO, USA.
authors: Nigel
authors: N
authors: Cairns
authors: Pathology and Immunology, Washington University, St. Louis, MO, USA.|Department of Neurology, Washington University, St. Louis, MO, USA.|Knight ADRC, Washington University, St. Louis, MO, USA.
authors: John C
authors: JC
authors: Morris
authors: Department of Biology, Brigham Young University, Provo, UT, 84602.
authors: John S K
authors: JSK
authors: Kauwe
authors: Department of Psychiatry, Washington University, St. Louis, MO, USA.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.|Department of Neurology, Washington University, St. Louis, MO, USA.|Knight ADRC, Washington University, St. Louis, MO, USA.|Department of Genetics, Washington University, St. Louis, MO, USA.
authors: Alison M
authors: AM
authors: Goate
mesh_terms: D001741:Black or African American / Q000235:genetics; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D005060:Europe / Q000208:ethnology; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D010739:Phospholipase D / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D059748:Proteolysis; D005090:Exodeoxyribonucleases
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D010739:Phospholipase D; C545487:APP protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C586092:PLD3 protein, human; D005090:Exodeoxyribonucleases