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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Amidohydrolases / genetics*
  • Amidohydrolases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Female
  • Frontal Lobe / metabolism
  • Frontal Lobe / pathology
  • Genome-Wide Association Study
  • Humans
  • Hydrogen Peroxide / metabolism
  • Linkage Disequilibrium / genetics
  • Male
  • Mice
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*


  • Amyloid beta-Peptides
  • Chromatin
  • Hydrogen Peroxide
  • Amidohydrolases
  • PM20D1 protein, human