PLD3 in Alzheimer’s Disease: a Modest Effect as Revealed by Updated Association and Expression Analyses

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. Numerous genome-wide association studies (GWASs) have found several AD susceptibility common loci but with limited effect size. Recent next-generation sequencing studies of large AD pedigrees had identified phospholipase D3 (PLD3) p.V232M as the potentially functional rare variant with causal effect. However, four follow-up replication studies (Brief Communications Arising on Nature) questioned that PLD3 V232M might not be so important in AD. In this study, we re-analyzed all public-available genetic (rare and common variants) and expression data of PLD3, and screened coding variants within PLD3 in probands of 18 Han Chinese families with AD, to clarify the exact involvement of PLD3 in AD. Two closest homologues of PLD3, PLD1 and PLD2, were also analyzed to comprehensively understand the role of phospholipase D members in AD. We found that PLD3 variant V232M was associated with AD risk in overall sample sets (∼40,000 subjects) with a modest to moderate effect size (odds ratio [OR] = 1.53). Our results also showed that common variants and mRNA expression alterations of PLD2 play a role in AD genetic risk and pathology. Although we provided a systematic view of the involvement of PLD3 in AD at the genetic, mRNA expression, and protein levels, we could not define the exact causal or essential role of PLD3 rare variants in AD based on currently available data.

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Acknowledgments

This work was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003). We thank the IGAP for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The iSelect chips were funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the Laboratory of Excellence Program Investment for the Future (LABEX) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant no. 503480), the Alzheimer’s Research UK (Grant no. 503176), the Wellcome Trust (Grant no. 082604/2/07/Z), and the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant nos. 01GI0102, 01GI0711, and 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, and U01 AG016976 and the Alzheimer’s Association grant ADGC–10–196728.

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The authors declare that they have no competing interests.

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Correspondence to Yong-Gang Yao.

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Zhang, DF., Fan, Y., Wang, D. et al. PLD3 in Alzheimer’s Disease: a Modest Effect as Revealed by Updated Association and Expression Analyses. Mol Neurobiol 53, 4034–4045 (2016). https://doi.org/10.1007/s12035-015-9353-5

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Keywords

  • Alzheimer’s disease
  • PLD3
  • Meta-analysis
  • Common variant
  • Rare variant