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Nature. 2014 Jan 23;505(7484):550-4. doi: 10.1038/nature12825. Epub 2013 Dec 11.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Author information

  • 11] 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.
  • 21] 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].
  • 31] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2].
  • 4Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.
  • 51] 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.
  • 6Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
  • 7Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF UK.
  • 8MRC Sudden Death Brain Bank Project, University of Edinburgh, South Bridge, Edinburgh EH8 9YL UK.
  • 91] 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.
  • 10Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK.
  • 11Istituto di Genetica delle Popolazioni - CNR, Trav. La Crucca, 3 - Reg. Baldinca - 07100 Li Punti, Sassari, Italy.
  • 12Department of Biology, Brigham Young University, Provo, Utah 84602, USA.
  • 131] Department of Mathematics and Statistics, Utah State University, Logan, Utah 84322, USA [2] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA.
  • 141] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA.
  • 151] 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.
  • 161] 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.
  • 17Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
  • 181] 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.
  • 19Department of Psychiatry, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
  • 20Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
  • 21Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
  • 22Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK.
  • 23University of Bonn, Regina-Pacis-Weg 3, 53113 Bonn, Germany.
  • 24University of Bristol, Tyndall Avenue, Bristol, City of Bristol BS8 1TH, UK.
  • 25University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, UK.
  • 26University of Newcastle, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK.
  • 27University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, UK.
  • 28University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK.
  • 291] 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.
  • 30Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pío XII, 55. 31008 Pamplona, Navarra, Spain.
  • 31University of Washington, 325 Ninth Avenue, Seattle, Washington 98104-2499, USA.
  • 32The Scripps Research Institute, La Jolla, California 3344 North Torrey Pines Court, La Jolla, California 92037, USA.
  • 33Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
  • 34Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
  • 351] 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.
  • 361] 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.
  • 371] 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.
  • 381] 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.
  • 391] 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.

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.

PMID:
24336208
[PubMed - indexed for MEDLINE]
PMCID:
PMC4050701
Free PMC Article

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