期刊
HUMAN MUTATION
卷 36, 期 12, 页码 1226-1235出版社
WILEY
DOI: 10.1002/humu.22908
关键词
Alzheimer dementia; EOAD; PLD3; next-generation sequencing; rare variants; meta-analysis
资金
- MetLife Foundation for Medical Research Award (USA)
- U. S. Army Medical Research and Material Command (USAMRMC) Research Award
- Janssen Pharmaceutical Stellar Research Project
- Belgian Science Policy Office Interuniversity Attraction Poles program
- Alzheimer Research Foundation (SAOFRA)
- Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research (VIND)
- Flemish Government initiated Methusalem Excellence Program
- Research Foundation Flanders (FWO)
- University of Antwerp Research Fund
- ISCIII, Cofinancia Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, Otra manera de hacer Europa [PI11/00234]
- Instituto de Salud Carlos III [PI12/01311]
- Grant Agency of Ministry of Health and Charles University Project [PRVOUK P26/1/4 (IGA NT12094-5)]
- Fundacao para a Ciencia e a Tecnologia [SFRH/BPD/29354/2006]
- Ricerca Corrente, Italian Ministry of Health
- the Cassa di Risparmio di Pistoia e Pescia [2014.0365]
- Cassa di Risparmio di Firenze [2014.0310]
- Ministry of Health [RF-2010-2319722]
- Swedish Brain Power, Swedish Research Council [521-2010-3134, A031340]
- King Gustaf V and Queen Victoria's Foundation of Freemasons
- Foundation of Marianne and Marcus Wallenberg
- Foundation of Knut and AliceWallenberg
- Foundation of Gun and Bertil Stohne
- Foundation of Gamla tjanarinnor
- Demensfonden Swedish Alzheimer Foundation [462081]
- StratNeuro at Karolinska Institute (KI)
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/29354/2006] Funding Source: FCT
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. Published 2015 Wiley Periodicals, Inc.
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