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Nat Med. 2018 May;24(5):598-603. doi: 10.1038/s41591-018-0013-y. Epub 2018 May 7.

PM20D1 is a quantitative trait locus associated with Alzheimer's disease.

Author information

1
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
2
Centro Nacional de Análisis Genómico (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
3
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
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.
5
Center for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain.
6
Bioinformatics Core Facility, Institute of Molecular Biology, Mainz, Germany.
7
Genomic Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Barcelona, Spain.
8
Institut de Biomedicina de València-CSIC, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Investigación Sanitaria 'La Fe', València, Spain.
9
Neurodegenerative Studies Laboratory, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
10
Cancer Epigenetics Group, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Barcelona, Spain.
11
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. johannes.graeff@epfl.ch.

Abstract

The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors 1 , the latter likely being mediated by epigenetic mechanisms 2 . In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology 3 , 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 GWAS 4 . 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.

PMID:
29736028
DOI:
10.1038/s41591-018-0013-y

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