Scientific publications

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

Dec 1, 2015 | Magazine: Human Mutation

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.


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