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


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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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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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).

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