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

AuthorsSánchez-Mut, José V.; Heyn, Holger; Silva, Bianca Ambrogina; Dixsaut, Lucie; Garcia-Esparcia, Paula; Vidal, Enrique; Sayols, Sergi; Glauser, Liliane; Monteagudo-Sánchez, Ana; Pérez-Tur, Jordi ; Ferrer, Isidre; Monk, David; Schneider, Bernard; Esteller, Manel; Gräff, Johannes
KeywordsAlzheimer's disease
Epigenetics and plasticity
Genetics of the nervous system
Issue Date7-May-2018
PublisherSpringer Nature
CitationNature Medicine 24(5):598-603 (2018)
AbstractThe chances to develop Alzheimer’s disease (AD) result from a combination of genetic and non-genetic risk factors1, the latter likely 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 thereof remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations and thereby provide mechanistic insights for a particular risk gene, but often lack the statistical power of GWAS4. Here, combining both approaches, we report a hitherto unidentified association of the Peptidase M20 domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation/expression quantitative trait locus (mQTL/eQTL) coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CTCF-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 AD patients, who are carriers of the non-risk haplotype. Importantly, genetically increasing and 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.
Description6 páginas, 3 figuras. En material suplementario 3 tablas, 7 figuras.
Publisher version (URL)http://dx.doi.org/10.1038/s41591-018-0013-y
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