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Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort

R. Cacace, T. Van den Bossche, S. Engelborghs, N. Geerts, A. Laureys, L. Dillen, C. Graff, H. Thonberg, HH. Chiang, P. Pastor, S. Ortega-Cubero, MA. Pastor, J. Diehl-Schmid, P. Alexopoulos, L. Benussi, R. Ghidoni, G. Binetti, B. Nacmias, S....

. 2015 ; 36 (12) : 1226-1235. [pub] 20151014

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc16028177

Grantová podpora
NT12094 MZ0 CEP - Centrální evidence projektů

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.

3rd Department of Neurology Medical School Aristotle University of Thessaloniki Makedonia Greece

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Department Hospital Clínic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

Center for Neuroscience and Cell Biology University of Coimbra Coimbra Portugal

Center of Clinical Neurosciences Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic

Center of Clinical Neurosciences Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic Institute of Pathology 3rd Medical Faculty of Charles University Prague Prague Czech Republic

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain Department of Neurology IIB Sant Pau Hospital de la Santa Creu i Sant Pau Universidad Autònoma de Barcelona Barcelona Spain

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas University of Navarra Pamplona Spain Department of Neurology Clínica Universidad de Navarra University of Navarra School of Medicine Pamplona Spain

Department of Geriatric Medicine Genetics Unit Karolinska University Hospital Stockholm Sweden

Department of Neurobiology Care Sciences and Society Center for Alzheimer Research Division of Neurogeriatrics Karolinska Institutet Huddinge Sweden Department of Geriatric Medicine Genetics Unit Karolinska University Hospital Stockholm Sweden

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium Department of Old Age Psychiatry and Memory Clinic University of Leuven Leuven Belgium

Department of Neurosciences Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Psychiatry and Psychotherapy Technische Universität München München Germany

Faculty of Medicine and Institute of Molecular Medicine University of Lisbon Lisbon Portugal

Institute Born Bunge University of Antwerp Antwerp Belgium Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium

Institute Born Bunge University of Antwerp Antwerp Belgium Department of Neurology Antwerp University Hospital Edegem Belgium

Laboratory of Biochemistry Department of Chemistry Aristotle University of Thessaloniki Thessaloniki Greece

Molecular Markers Laboratory Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

Neurodegenerative Brain Diseases Group Department of Molecular Genetics VIB Antwerp Belgium Institute Born Bunge University of Antwerp Antwerp Belgium

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 Edegem Belgium

Neurogenetics Laboratory Division of Neurosciences Center for Applied Medical Research Universidad de Navarra Pamplona Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain

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 Instituto de Salud Carlos 3 Madrid Spain

Neurological Tissue Bank of the Biobanc Hospital Clinic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

Neurology Unit University of Brescia Brescia Italy

Citace poskytuje Crossref.org

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$a 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.
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