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

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. 49 post-mortem brain (striatum, putamen) samples were obtained from the London Brain Bank for Neurodegenerative Disorders (LBBND; 21 schizophrenia and 28 controls), London, UK. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.