Role of PLD3 rare variants in european sporadic Alzheimer's disease patients.

Abstract

Background: Alzheimer's disease (AD) is a severe multifactorial disorder and the individual genetic predisposition plays a decisive role in its etiology. While genome-wide association studies have been successful in identifying common genetic risk factors for AD, w hole exome sequencing provides a promising strategy to identify rare coding variants that increase the risk for familial but may also confer risk for sporadic AD (sAD). This led to the identification of TREM2 and PLD3 - as novel susceptibility genes.While TREM2 has been repeatedly replicated as a risk factor in sAD, the role of PLD3 in sAD has not yet been replicated. Thus, we aimed to investigate a potential role of rare coding variants in PLD3 in sAD in two independent samples of German and Spanish origin comprising a total 6,921 individuals. Methods: The independent Spanish and German case-control samples comprised 2,427 cases and 2,614 controls and 940 cases and 940 controls, respectively. All AD patients fulfilled NINCDA/ADRDA criteria. All participants gave written informed consent. Four variants reported by Cruchaga et al. with p<0.15 were selected for genotyping using Sequenom's iPLEX-assay. Association analysis was calculated by applying the Armitage trend test as implemented in INTERSNP. Association was also analysed after stratifying AD cases by age at disease onset (AAO) or familial history of AD. Results: Neither the analyses in the individual samples nor the combined analysis supported the association between sAD and the PLD3 variants investigated. The combined analysis showed for: p.P76A (p=0.16, OR=4.27); p. V232M (p= 0.44, OR=0.8); and p.A442A (p=0.66, OR=1.06). The p.M6Rwasmonomorphic. The original association of PLD3 was described in late onset AD (LOAD, AAO>65 years). However, neither the LOAD sample nor the early onset AD (AAO<65) showed association with AD-risk in the stratified analysis. The association with AD was also negative after stratifying the samples for familial history of AD. Conclusions: Our results do not support the role of rare coding variants in PLD3 in the susceptibility to suffer sAD in two independent European populations, even when stratifying by AAO or familial history of AD. We are currently genotyping additional case-control samples to include in the analysis