title: Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.
abstract: Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Cacace
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
authors.forename: Tobi
authors.initials: T
authors.lastname: Van den Bossche
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Geerts
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Laureys
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Lubina
authors.initials: L
authors.lastname: Dillen
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.|Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.|Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.affiliation: Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Huei-Hsin
authors.initials: HH
authors.lastname: Chiang
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain.|Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pastor
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Diehl-Schmid
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors.forename: Panagiotis
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authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Roberta
authors.initials: R
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authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Giuliano
authors.initials: G
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authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Valle
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
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authors.affiliation: Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria Rosário
authors.initials: MR
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authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel
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authors.affiliation: 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Makedonia, Greece.
authors.forename: Magda
authors.initials: M
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authors.affiliation: Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Koutroumani
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimon
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
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authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
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authors.affiliation: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Mendonça
authors.affiliation: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Madalena
authors.initials: M
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authors.affiliation: Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
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authors.affiliation: Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: Center of Clinical Neurosciences, Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic.|Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Matej
authors.affiliation: Center of Clinical Neurosciences, Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic.|Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.|Institute of Pathology, Third Medical Faculty of Charles University in Prague, Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Rohan
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Department of Old Age Psychiatry and Memory Clinic, University of Leuven, Leuven, Belgium.
authors.forename: Mathieu
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authors.lastname: Vandenbulcke
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
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authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
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mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D059472:Exome; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D010739:Phospholipase D / Q000235:genetics*; D012306:Risk; D005090:Exodeoxyribonucleases
chemical_list: D010739:Phospholipase D; C586092:PLD3 protein, human; D005090:Exodeoxyribonucleases
keywords: Alzheimer dementia; EOAD; PLD3; meta-analysis; next-generation sequencing; rare variants