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PM20D1 is a quantitative trait locus associated with Alzheimer’s disease

Nature Medicine volume 24, pages 598–603 (2018)Cite this article

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Abstract

The chances to develop Alzheimer’s disease (AD) result from a combination of genetic and non-genetic risk factors1, the latter likely being mediated by epigenetic mechanisms2. In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology3, but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS4. Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.

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Fig. 1: Overview of the PM20D1 locus and its relation to AD in human frontal cortex.
Fig. 2: Long-range chromatin interaction of the rs708727–PM20D1 locus.
Fig. 3: Functional relevance of PM20D1 in AD.

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Acknowledgements

The work in the laboratory of J.G. is supported by the SYNAPSIS Foundation, the Béatrice Ederer-Weber Stiftung, the Floshield Foundation and the Alzheimer’s Association (grant no. NIRG-15-363964). The laboratory of D.M. is supported by the Foundation Jérôme Lejeune, Spanish Ministerio de Educación y Competitividad (grant no. BFU2014-53093). The laboratory of J.P.-T. is supported by the Spanish Ministerio de Economía, Industria y Competitividad and the FEDER programme from the EU (grant no. SAF2014-59469-R) and the CIBERNED. J.V.S.-M. is supported by a SYNAPSIS Foundation Fellowship for Advanced PostDocs and the Heidi Seiler-Stiftung foundation. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). B.A.S. is an EMBO long-term fellow (ALTF 1605-2014, Marie Curie Actions, LTFCOFUND2013, GA-2013-609409). A.M.-S. is a recipient of a FPI PhD studentship from MINECO. M.E. is an ICREA Research Professor. J.G. is an MQ fellow and a NARSAD Independent Investigator.

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Authors and Affiliations

  1. Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Jose V. Sanchez-Mut, Bianca A. Silva, Lucie Dixsaut, Liliane Glauser & Johannes Gräff

  2. Centro Nacional de Análisis Genómico (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    Holger Heyn

  3. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Holger Heyn

  4. Department of Pathology and Experimental Therapeutics, University of Barcelona, Institut d’Investigació Biomedica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Paula Garcia-Esparcia & Isidre Ferrer

  5. Center for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain

    Enrique Vidal

  6. Bioinformatics Core Facility, Institute of Molecular Biology, Mainz, Germany

    Sergi Sayols

  7. Genomic Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Barcelona, Spain

    Ana Monteagudo-Sánchez & David Monk

  8. Institut de Biomedicina de València–CSIC, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Investigación Sanitaria ‘La Fe’, València, Spain

    Jordi Perez-Tur

  9. Neurodegenerative Studies Laboratory, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Bernard Schneider

  10. Cancer Epigenetics Group, Cancer Epigenetics and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Barcelona, Spain

    Manel Esteller

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Contributions

J.V.S.-M., H.H., M.E. and J.G. conceived the project and designed the experiments; J.V.S.-M., B.A.S., L.D., P.G.-E., L.G., A.M.-S. and D.M. performed the experiments; J.V.S.-M., E.V. and S.S. performed the bioinformatics analysis of the data; J.P.-T., I.F., B.S., D.M. and M.E. contributed to the interpretation of the results; and J.V.S.-M. and J.G. wrote the paper, with input and comments by all of the authors.

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Correspondence to Johannes Gräff.

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A provisional patent application has been filed on the use of PM20D1 methylation and haplotype as biomarkers for Alzheimer’s disease (International Application Number PCT/EP2017/067848), with J.V.S.-M., H.H., M.E. and J.G. listed as inventors.

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Sanchez-Mut, J.V., Heyn, H., Silva, B.A. et al. PM20D1 is a quantitative trait locus associated with Alzheimer’s disease. Nat Med 24, 598–603 (2018). https://doi.org/10.1038/s41591-018-0013-y

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