@article{045ce150f50e4d2d8ca086e11415fd5d,
title = "Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex",
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. (C) 2020 Published by Elsevier Inc.",
keywords = "Alzheimer's disease, Brain, DNA methylation, Epigenetics, Psychosis, Schizophrenia, SCHIZOPHRENIA, METHYLATION, HERITABILITY, RISK",
author = "Ehsan Pishva and Byron Creese and Smith, {Adam R.} and Wolfgang Viechtbauer and Petroula Proitsi and {van den Hove}, {Daniel L. A.} and Clive Ballard and Jonathan Mill and Katie Lunnon",
note = "Funding Information: This work was funded by an Alzheimer's Association US New Investigator Research Grant (NIRG- 14-320878 ) to KL, a major project grant from the Alzheimer's Society UK ( AS-PG-14-038 ) to KL, a grant from the Joint Programme—Neurodegenerative Disease Research (JPND) for the EPI-AD consortium to EP, DvDH and KL, a NIH R01 grant ( AG036039 ) to JM and an Equipment Grant from Alzheimer's Research UK ( ART-EG2010A-2 ) to JM. The authors thank all the donors and families who have made this research possible. Brain tissue was received from the LNDBB. Funding Information: This work was funded by an Alzheimer's Association US New Investigator Research Grant (NIRG-14-320878) to KL, a major project grant from the Alzheimer's Society UK (AS-PG-14-038) to KL, a grant from the Joint Programme?Neurodegenerative Disease Research (JPND) for the EPI-AD consortium to EP, DvDH and KL, a NIH R01 grant (AG036039) to JM and an Equipment Grant from Alzheimer's Research UK (ART-EG2010A-2) to JM. The authors thank all the donors and families who have made this research possible. Brain tissue was received from the LNDBB. This study used epigenome-wide association study (EWAS) Illumina 450K DNA methylation data that had already been generated in human postmortem brain tissue from donors in the MRC London Neurodegenerative Disease Brain Bank and these data are available on GEO. In the course of this study, the authors also generated pyrosequencing data using the DNA that had been isolated for that EWAS. Ethical approval for our project was awarded by the University of Exeter Medical School research ethics committee. Authors' contributions: EP contributed to conceptualization, methodology, software, writing?original draft, writing?review and editing preparation, formal analysis, and investigation. BC contributed to conceptualization, writing?original draft preparation, writing?review and editing, formal analysis, and investigation. ARS contributed to investigation and validation. WV contributed to methodology. PP contributed to resources. DLAvdH contributed to funding acquisition and supervision. CB contributed to conceptualization and resources. JM contributed to funding acquisition, supervision, writing?review and editing, and resources. KL contributed to conceptualization, writing?original draft, writing?review and editing, supervision, project administration, and funding acquisition. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = may,
doi = "10.1016/j.neurobiolaging.2020.01.001",
language = "English",
volume = "89",
pages = "83--88",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Science",
}