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  • Brief Communications Arising
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PLD3 gene variants and Alzheimer's disease

Nature volume 520, pages E7–E8 (2015)Cite this article

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arising from C. Cruchaga et al. Nature 505, 550–554 (2014); doi:10.1038/nature12825

Cruchaga et al. recently reported1 evidence for genetic association between Alzheimer's disease risk and several rare DNA sequence variants in the phospholipase D3 gene (PLD3). The study's lead signal Val232Met (rs145999145) co-segregated with Alzheimer's disease in multiple affected families, and also showed association with Alzheimer's disease risk in case–control samples; whereas two other highly conserved PLD3 variants, Ala442Ala (rs4819) and Met6Arg, showed nominal association with disease risk. Our efforts to replicate these findings in a large collection of family-based Alzheimer's disease data failed to reveal any risk effect of PLD3 in Alzheimer's disease. Our negative results, taken together with equally negative companion reports2,3,4 and recent GWAS meta-analysis results5, call for additional studies to examine the proposed role, if any, of rare variants in PLD3 on Alzheimer's disease risk. There is a Reply to this Brief Communication Arising by Cruchaga, C. & Goate, A. M. Nature 520, http://dx.doi.org/10.1038/nature14041 (2015).

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Figure 1: Forest plots of study-specific odds ratios of case–control data sets assessing the potential association between Alzheimer's disease risk and Val232Met (rs145999145) (a) or Ala442Ala (rs4819) (b).
Figure 2: Appendix Figure 1

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Author information

Author notes

  1. Basavaraj V. Hooli and Christina M. Lill: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Basavaraj V. Hooli, Kristina Mullin & Rudolph E. Tanzi

  2. Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, 23552 Lübeck, Germany

    Christina M. Lill & Lars Bertram

  3. Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany

    Christina M. Lill

  4. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany

    Christina M. Lill & Lars Bertram

  5. Department of Biostatistics, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Dandi Qiao & Christoph Lange

  6. School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London W6 8RP, UK,

    Lars Bertram

Authors
  1. Basavaraj V. Hooli
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  2. Christina M. Lill
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Contributions

R.E.T., L.B., B.V.H. and C.M.L. designed the study; B.V.H. and K.M. generated data; C.M.L., D.Q. and C.L. performed statistical analyses; B.V.H., L.B., C.M.L. and R.E.T. wrote the paper.

Corresponding authors

Correspondence to Lars Bertram or Rudolph E. Tanzi.

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Declared none.

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Hooli, B., Lill, C., Mullin, K. et al. PLD3 gene variants and Alzheimer's disease. Nature 520, E7–E8 (2015). https://doi.org/10.1038/nature14040

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