Cacace, RitaVan den Bossche, TobiEngelborghs, SebastiaanGeerts, NathalieLaureys, AnneliesDillen, LubinaGraff, CarolineThonberg, HåkanChiang, Huei-HsinPastor, PauOrtega-Cubero, SaraPastor, Maria A.Diehl-Schmid, JanineAlexopoulos, PanagiotisBenussi, LuisaGhidoni, RobertaBinetti, GiulianoNacmias, BenedettaSorbi, SandroSanchez-Valle, RaquelLladó, AlbertGelpi, EllenAlmeida, Maria RosárioSantana, IsabelTsolaki, MagdaKoutroumani, MariaClarimon, JordiLleó, AlbertoFortea, JuanDe Mendonça, AlexandreMartins, MadalenaBorroni, BarbaraPadovani, AlessandroMatej, RadoslavRohan, ZdenekVandenbulcke, MathieuVandenberghe, RikDe Deyn, Peter P.Cras, Patrickvan der Zee, JulieSleegers, KristelVan Broeckhoven, Christine2022-06-232022-06-232015Hum Mutat. 2015 Dec;36(12):1226-12351059-7794http://hdl.handle.net/10451/53458© 2015 The Authors. ∗∗ Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.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.engAlzheimer dementiaEOADPLD3Meta-analysisNext-generation sequencingRare variantsjournal article10.1002/humu.229081098-1004