title: Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions.
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.
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Viana
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Dempster
authors.affiliation: Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Ruby
authors.initials: R
authors.lastname: Macdonald
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Knox
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Spiers
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Saraj
authors.affiliation: Douglas Mental Health Institute, McGill University, Montreal, QC, Canada and.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, UK.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.|Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002102:Cadaver; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D017397:Prefrontal Cortex / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D015415:Biomarkers