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PMID: 24336208 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature ·Vol. 505 ·No. 7484 ·2014-01-23 ·Pages 550-554

Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, Sassi C, Bras J, Gibbs RJ, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Alzheimer's Research UK ARUK Consortium, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton A, Hardy J, Kamboh MI, George-Hyslop PS, Cairns N, Morris JC, Kauwe JSK, Goate AM

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.

MeSH Terms
African Americans/genetics Age of Onset Aged Aged, 80 and over Alzheimer Disease/genetics,metabolism Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/metabolism Brain/metabolism Case-Control Studies Europe/ethnology Exome/genetics Female Genetic Predisposition to Disease/genetics Genetic Variation/genetics Humans Male Peptide Fragments/metabolism Phospholipase D/deficiency,genetics,metabolism Protein Processing, Post-Translational/genetics Proteolysis
Chemicals
APP protein, human Amyloid beta-Peptides Amyloid beta-Protein Precursor Peptide Fragments amyloid beta-protein (1-40) amyloid beta-protein (1-42) Phospholipase D phospholipase D3, human
Authors & Affiliations
59 authors, click to expand affiliations / ORCID
Cruchaga Carlos
Department of Psychiatry, Washington University, St. Louis, MO, USA. | Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
Karch Celeste M
Department of Psychiatry, Washington University, St. Louis, MO, USA. | Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
Jin Sheng Chih
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Benitez Bruno A
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Cai Yefei
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Guerreiro Rita
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 Oscar
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Norton Joanne
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Budde John
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Bertelsen Sarah
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Jeng Amanda T
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Cooper Breanna
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Skorupa Tara
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Carrell David
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Levitch Denise
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Hsu Simon
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Choi Jiyoon
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Ryten Mina
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. | on behalf of UKBEC (UK Brain Expression Consortium).
Sassi Celeste
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 Jose
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Gibbs Raphael J
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 Dena G
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 Michelle K
Institute of Psychiatry, King's College London, London, UK. | Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Powell John
Institute of Psychiatry, King's College London, London, UK.
Forabosco Paola
Istituto di Genetica delle Popolazioni - CNR, Sassari, Italy.
Ridge Perry G
Department of Biology, Brigham Young University, Provo, UT, 84602.
Corcoran Christopher D
Department of Mathematics and Statistics, Utah State University, Logan, UT. | Center for Epidemiologic Studies, Utah State University, Logan, UT.
Tschanz JoAnn T
Center for Epidemiologic Studies, Utah State University, Logan, UT. | Department of Psychology, Utah State University, Logan, UT.
Norton Maria C
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 Ronald G
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 Cameron
Department of Biology, Brigham Young University, Provo, UT, 84602.
Leary Maegan
Department of Biology, Brigham Young University, Provo, UT, 84602.
Demirci F Yesim
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Bamne Mikhil N
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Wang Xingbin
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Lopez Oscar L
Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA. | Department of Neurology, University of Pittsburgh, Pittsburgh, PA.
Ganguli Mary
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
Medway Christopher
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Turton James
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Lord Jenny
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Braae Anne
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Barber Imelda
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Brown Kristelle
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Alzheimer's Research UK (ARUK) Consortium
Pastor Pau
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 Oswaldo
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Brkanac Zoran
University of Washington. Seattle, WA.
Scott Erick
The Scripps Research Institute, La Jolla, CA, US.
Topol Eric
The Scripps Research Institute, La Jolla, CA, US.
Morgan Kevin
Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
Rogaeva Ekaterina
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto.
Singleton Andy
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
Hardy John
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Kamboh M Ilyas
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 Peter St
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 Nigel
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA. | Pathology and Immunology, Washington University, St. Louis, MO, USA.
Morris John C
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 John S K
Department of Biology, Brigham Young University, Provo, UT, 84602.
Goate Alison M
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.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature12825
Published
2014-01-23
Epub
2013-00-11
Pages
550-554
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4050701
Subset
IM
Grants
Medical Research Council · G0802189 · United Kingdom
NIA NIH HHS · R01 AG042611 · United States
CIHR · Canada
Wellcome Trust · 089703 · United Kingdom
NIA NIH HHS · U24 AG026395 · United States
NIA NIH HHS · R01 AG041797 · United States
NIA NIH HHS · RF1 AG044546 · United States
NIA NIH HHS · R01 AG030653 · United States
NIA NIH HHS · R01 AG021136 · United States
Wellcome Trust · 100140 · United Kingdom
NIA NIH HHS · R01 AG039700 · United States
Medical Research Council · G0901254 · United Kingdom
NIA NIH HHS · ZO1AG000950-11 · United States
NIA NIH HHS · R01AG21136 · United States
NIA NIH HHS · R01-AG042611 · United States
NIA NIH HHS · R01-AG11380 · United States
NIA NIH HHS · AG07562 · United States
NIA NIH HHS · 1R01AG041797 · United States
NIA NIH HHS · R01 AG044546 · United States
NIA NIH HHS · U24 AG021886 · United States
NIA NIH HHS · ZO1 AG000950-10 · United States
Intramural NIH HHS · ZIA AG000950-11 · United States
Medical Research Council · MR/L016400/1 · United Kingdom
NIA NIH HHS · P01 AG003991 · United States
NIA NIH HHS · P50 AG005681 · United States
NIA NIH HHS · U24 AG056270 · United States
NIA NIH HHS · R01-AG21136 · United States
NIA NIH HHS · 5U24AG026395 · United States
NIA NIH HHS · P01 AG026276 · United States
NINDS NIH HHS · P30-NS069329 · United States
NIA NIH HHS · U24AG21886 · United States
NIA NIH HHS · P01 AG03991 · United States
Medical Research Council · MC_G1000735 · United Kingdom
PHS HHS · NIH R01039700 · United States
NIA NIH HHS · AG041718 · United States
Medical Research Council · G1100695 · United Kingdom
NIA NIH HHS · NIH P50 AG05681 · United States
Intramural NIH HHS · Z01 AG000950 · United States
Wellcome Trust · 089698 · United Kingdom
NIA NIH HHS · R01-AG18712 · United States
NIA NIH HHS · K01 AG046374 · United States
NIA NIH HHS · AG023652 · United States
NIA NIH HHS · R01-AG035083 · United States
NIA NIH HHS · AG030653 · United States
NIA NIH HHS · R01-AG044546 · United States
NIA NIH HHS · P50 AG005133 · United States
NIA NIH HHS · R01 AG041718 · United States
NIDA NIH HHS · R25 DA027995 · United States
NINDS NIH HHS · P30 NS069329 · United States
NIA NIH HHS · AG005133 · United States
Wellcome Trust · 081864 · United Kingdom
NIA NIH HHS · R01 AG011380 · United States
Medical Research Council · MC_G1000734 · United Kingdom
NIA NIH HHS · R01 AG035083 · United States
NIA NIH HHS · R01 AG018712 · United States
Medical Research Council · G0802462 · United Kingdom
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External Links
PubMed source DOI: 10.1038/nature12825 PMC Full Text View journal details
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