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: Rita Cacace, Tobi Van den Bossche, Sebastiaan Engelborghs, Nathalie Geerts, Annelies Laureys, Lubina Dillen, Caroline Graff, Håkan Thonberg, Huei-Hsin Chiang, Pau Pastor, Sara Ortega-Cubero, Maria A Pastor, Janine Diehl-Schmid, Panagiotis Alexopoulos, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Benedetta Nacmias, Sandro Sorbi, Raquel Sanchez-Valle, Albert Lladó, Ellen Gelpi, Maria Rosário Almeida, Isabel Santana, Magda Tsolaki, Maria Koutroumani, Jordi Clarimon, Alberto Lleó, Juan Fortea, Alexandre de Mendonça, Madalena Martins, Barbara Borroni, Alessandro Padovani, Radoslav Matej, Zdenek Rohan, Mathieu Vandenbulcke, Rik Vandenberghe, Peter P De Deyn, Patrick Cras, Julie van der Zee, Kristel Sleegers, Christine Van Broeckhoven, Belgium Neurology (BELNEU) Consortium and the European Early-Onset Dementia (EU EOD) Consortium
• Journal: Human mutation (Hum Mutat) Vol. 36 Issue 12 Pg. 1226-35 (Dec 2015) ISSN: 1098-1004 [Electronic] United States
• PMID: 26411346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Chemical References

• PLD3 protein, human
• Phospholipase D

Topics

• Adult
• Age of Onset
• Aged
• Alleles
• Alternative Splicing
• Alzheimer Disease (epidemiology, genetics)
• Case-Control Studies
• Cohort Studies
• Europe (epidemiology)
• Exome
• Genetic Predisposition to Disease
• Genetic Variation
• High-Throughput Nucleotide Sequencing
• Humans
• Meta-Analysis as Topic
• Middle Aged
• Odds Ratio
• Phospholipase D (genetics)
• Risk