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

Sanchez-Mut, Jose V., Heyn, Holger, Silva, Bianca A., Dixsaut, Lucie, Garcia-Esparcia, Paula, Vidal, Enrique, Sayols, Sergi, Glauser, Liliane, Monteagudo-Sánchez, Ana, Perez-Tur, Jordi, Ferrer, Isidre, Monk, David, Schneider, Bernard, Esteller, Manel and Gräff, Johannes (2018) PM20D1 is a quantitative trait locus associated with Alzheimer’s disease. Nature Medicine, 24 (5). pp. 598-603. ISSN 1078-8956

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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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 28 Nov 2020 00:49
Last Modified: 22 Oct 2022 07:26
DOI: 10.1038/s41591-018-0013-y

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