Scientific publications

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

Cacace R (1,2), Van den Bossche T (1,2,3), Engelborghs S (2,4), Geerts N (1,2), Laureys A (1,2), Dillen L (1,2), Graff C (5,6), Thonberg H (5,6), Chiang HH (6), Pastor P (7,8,9), Ortega-Cubero S (7,9), Pastor MA (9,10,11), Diehl-Schmid J (12), Alexopoulos P (12), Benussi L (13), Ghidoni R (13), Binetti G (13), Nacmias B (14), Sorbi S (14), Sanchez-Valle R (15), Lladó A (15), Gelpi E (16), Almeida MR (17), Santana I (17), Tsolaki M (18), Koutroumani M (19), Clarimon J (9,20), Lleó A (9,20), Fortea J (9,20), de Mendonça A (21), Martins M (21), Borroni B (22), Padovani A (22), Matej R (23,24), Rohan Z (23,24,25), Vandenbulcke M (26,27), Vandenberghe R (26,28), De Deyn PP (2,4), Cras P (2,3), van der Zee J (1,2), Sleegers K (1,2), Van Broeckhoven C 1,2; Belgium Neurology (BELNEU) Consortium and the European Early-Onset Dementia (EU EOD) Consortium.
(1) Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
(2) Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
(3) Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
(4) Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
(5) Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
(6) Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
(7) Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain.
(8) Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain.
(9) Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
(10) Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
(11) Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
(12) Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
(13) Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
(14) Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
(15) Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(16) Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(17) Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
(18) 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Makedonia, Greece.
(19) Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
(20) Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
(21) Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
(22) Neurology Unit, University of Brescia, Brescia, Italy.
(23) Center of Clinical Neurosciences, Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic.
(24) Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.
(25) Institute of Pathology, Third Medical Faculty of Charles University in Prague, Prague, Czech Republic.
(26) Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.
(27) Department of Old Age Psychiatry and Memory Clinic, University of Leuven, Leuven, Belgium.
(28) Department of Neurology, University Hospitals Leuven, Leuven, Belgium. 

Magazine: Human Mutation

Date: Dec 1, 2015

Neurology [SP]


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.

CITATION  Hum Mutat. 2015 Dec;36(12):1226-35. doi: 10.1002/humu.22908. Epub 2015 Oct 14

you maybe interested


The Clínica is the greater private hospital with technological equipment of Spain, all in a single center.

Imagen de un PET, tecnología de vanguardia en la Clínica Universidad de Navarra


The professionals of the Clínica perform continuous research and training, always to the benefit of the patient.

Imagen profesionales de la Clínica Universidad de Navarra


Learn why we are different from other healthcare centers. Quality, speed, comfort and results.

Imagen del edificio de la Clínica Universidad de Navarra