Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex

Neurobiol Aging. 2020 May;89:83-88. doi: 10.1016/j.neurobiolaging.2020.01.001. Epub 2020 Jan 8.

Abstract

Psychotic symptoms are a common and debilitating feature of Alzheimer's disease (AD) and are associated with a more rapid course of decline. Current evidence from postmortem and neuroimaging studies implicates frontal, temporal, and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in 3 key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex, and superior temporal gyrus) in postmortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in the AS3MT gene-previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across 4 neighboring CpG sites in the ASM3T gene. Finally, our regional analysis nominated multiple CpG sites in TBX15 and WT1, which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies.

Keywords: Alzheimer's disease; Brain; DNA methylation; Epigenetics; Psychosis; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Biogenic Monoamines / metabolism
  • Cerebral Cortex / metabolism*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic
  • Genetic Variation / genetics
  • Humans
  • Methyltransferases / genetics
  • Psychotic Disorders / etiology
  • Psychotic Disorders / genetics*
  • Schizophrenia / etiology
  • Schizophrenia / genetics
  • T-Box Domain Proteins / genetics
  • WT1 Proteins / genetics

Substances

  • Biogenic Monoamines
  • T-Box Domain Proteins
  • TBX15 protein, human
  • WT1 Proteins
  • WT1 protein, human
  • Methyltransferases
  • AS3MT protein, human