| First Author | Sanchez-Mut JV | Year | 2018 |
| Journal | Nat Med | Volume | 24 |
| Issue | 5 | Pages | 598-603 |
| PubMed ID | 29736028 | Mgi Jnum | J:271611 |
| Mgi Id | MGI:6278237 | Doi | 10.1038/s41591-018-0013-y |
| Citation | Sanchez-Mut JV, et al. (2018) PM20D1 is a quantitative trait locus associated with Alzheimer's disease. Nat Med 24(5):598-603 |
| abstractText | 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. |
