Schizophrenia-associated methylomic variation

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

Joana Viana1, Eilis Hannon1, Emma Dempster1, Ruth Pidsley2, Ruby Macdonald1, Olivia Knox1, Helen Spiers3, Claire Troakes3, Safa Al-Saraj3, Gustavo Turecki4, Leonard C Schalkwyk5, Jonathan Mill1,3,*

1 University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
2 Garvan Institute of Medical Research, Sydney 2010, NSW, Australia.
3 Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, SE5 8AF, UK.
4 Douglas Mental Health Institute, McGill University, Montreal H4H 1R3, QC, Canada.
5 School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK.
 

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 etiology 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, many residing in the vicinity of genes previously implicated in schizophrenia including NCAM1, SYNPO, GBP4, PRDM9, GADD45B and DISC1. 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 etiological variation in complex disease.

phenotype.csv shows the phenotype information matching the samples included in the analyses (data available on GEO)
CER case control EWAS meta-analysis.csv shows the results of the schizophrenia case control EWAS meta-analaysis for all probes in the cerebellum
CER polygenic risk score EWAS meta-analysis.csv shows the results of the schizophrenia polygenic risk score EWAS meta-analaysis for all probes in the cerebellum
HC case control EWAS.csv shows the results of the schizophrenia case control EWAS for all probes in the hippocampus
HC polygenic risk score EWAS.csv shows the results of the schizophrenia polygenic risk score EWAS for all probes in the hippocampus
Multilevel model case control EWAS.csv shows the results of the cross-brain region schizophrenia EWAS including data from the prefrontal cortex, striaum and hippocampus
Multilevel model polygenic risk score EWAS.csv shows the results of the cross-brain region schizophrenia polygenic risk score EWAS including data from the prefrontal cortex, striaum and hippocampus
PFC case control EWAS meta-analysis.csv shows the results of the schizophrenia case control EWAS meta-analysis for all probes in the prefrontal cortex
PFC polygenic risk score EWAS meta-analysis.csv shows the results of the schizophrenia polygenic risk score EWAS meta-analysis for all probes in the prefrontal cortex
STR case control EWAS meta-analysis.csv hows the results of the schizophrenia case control EWAS meta-analysis for all probes in the striatum
STR polygenic risk score EWAS meta-analysis.csv hows the results of the schizophrenia polygenic risk score EWAS meta-analysis for all probes in the striatum