Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions.

TitleSchizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions.
Publication TypeJournal Article
Year of Publication2017
AuthorsViana J, Hannon E, Dempster E, Pidsley R, Macdonald R, Knox O, Spiers H, Troakes C, Al-Saraj S, Turecki G, Schalkwyk LC, Mill J
JournalHum Mol Genet
Volume26
Issue1
Pagination210-225
Date Published2017 Jan 01
ISSN1460-2083
Abstract

Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease.

DOI10.1093/hmg/ddw373
Alternate JournalHum. Mol. Genet.
PubMed ID28011714
PubMed Central IDPMC5351932
Grant ListMR/K013807/1 / / Medical Research Council / United Kingdom