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

Autor: Cruchaga C; Department of Psychiatry, Washington University, St. Louis, MO, USA.; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA., Karch CM; Department of Psychiatry, Washington University, St. Louis, MO, USA.; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA., Jin SC; Department of Psychiatry, Washington University, St. Louis, MO, USA., Benitez BA; Department of Psychiatry, Washington University, St. Louis, MO, USA., Cai Y; Department of Psychiatry, Washington University, St. Louis, MO, USA., Guerreiro R; 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., Harari O; Department of Psychiatry, Washington University, St. Louis, MO, USA., Norton J; Department of Psychiatry, Washington University, St. Louis, MO, USA., Budde J; Department of Psychiatry, Washington University, St. Louis, MO, USA., Bertelsen S; Department of Psychiatry, Washington University, St. Louis, MO, USA., Jeng AT; Department of Psychiatry, Washington University, St. Louis, MO, USA., Cooper B; Department of Psychiatry, Washington University, St. Louis, MO, USA., Skorupa T; Department of Psychiatry, Washington University, St. Louis, MO, USA., Carrell D; Department of Psychiatry, Washington University, St. Louis, MO, USA., Levitch D; Department of Psychiatry, Washington University, St. Louis, MO, USA., Hsu S; Department of Psychiatry, Washington University, St. Louis, MO, USA., Choi J; Department of Psychiatry, Washington University, St. Louis, MO, USA., Ryten M; Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.; on behalf of UKBEC (UK Brain Expression Consortium)., Sassi C; 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., Bras J; Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK., Gibbs RJ; 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., Hernandez DG; 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., Lupton MK; Institute of Psychiatry, King's College London, London, UK.; Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Powell J; Institute of Psychiatry, King's College London, London, UK., Forabosco P; Istituto di Genetica delle Popolazioni - CNR, Sassari, Italy., Ridge PG; Department of Biology, Brigham Young University, Provo, UT, 84602., Corcoran CD; Department of Mathematics and Statistics, Utah State University, Logan, UT.; Center for Epidemiologic Studies, Utah State University, Logan, UT., Tschanz JT; Center for Epidemiologic Studies, Utah State University, Logan, UT.; Department of Psychology, Utah State University, Logan, UT., Norton MC; 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., Munger RG; Department of Family Consumer and Human Development, Utah State University, Logan, UT.; Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT., Schmutz C; Department of Biology, Brigham Young University, Provo, UT, 84602., Leary M; Department of Biology, Brigham Young University, Provo, UT, 84602., Demirci FY; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA., Bamne MN; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA., Wang X; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA., Lopez OL; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.; Department of Neurology, University of Pittsburgh, Pittsburgh, PA., Ganguli M; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA., Medway C; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Turton J; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Lord J; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Braae A; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Barber I; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Brown K; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Pastor P; 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., Lorenzo-Betancor O; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain., Brkanac Z; University of Washington. Seattle, WA., Scott E; The Scripps Research Institute, La Jolla, CA, US., Topol E; The Scripps Research Institute, La Jolla, CA, US., Morgan K; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK., Rogaeva E; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto., Singleton A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Hardy J; Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK., Kamboh MI; 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., George-Hyslop PS; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto.; Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge., Cairns N; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.; Pathology and Immunology, Washington University, St. Louis, MO, USA., Morris JC; 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., Kauwe JSK; Department of Biology, Brigham Young University, Provo, UT, 84602., Goate AM; 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.
Jazyk: angličtina
Zdroj: Nature [Nature] 2014 Jan 23; Vol. 505 (7484), pp. 550-554. Date of Electronic Publication: 2013 Dec 11.
DOI: 10.1038/nature12825
Abstrakt: 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.
Databáze: MEDLINE