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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.

SUBMITTER: Viana J

PROVIDER: S-EPMC5351932 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and hypothesisSchizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures. We expected consistent evidence to emerge for significant sczPRS associations with variation in structure and function, specifically in frontal, temporal, and insula cortices that are commonly implicated in schizophrenia pathophysiology.Study designIn accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, and PsycINFO for peer-reviewed studies published between January 2013 and March 2022. Studies were screened against predetermined criteria and National Institutes of Health (NIH) quality assessment tools.Study resultsIn total, 57 studies of T1-weighted structural, diffusion, and functional MRI were included (age range = 9-80 years, Nrange = 64-76 644). We observed moderate, albeit preliminary, evidence for higher sczPRS predicting global reductions in cortical thickness and widespread variation in functional connectivity, and to a lesser extent, region-specific reductions in frontal and temporal volume and thickness. Conversely, sczPRS does not predict whole-brain surface area or gray/white matter volume. Limited evidence emerged for sczPRS associations with diffusion tensor measures of white matter microstructure in a large community sample and smaller cohorts of children and young adults. These findings were broadly consistent across community and clinical populations.ConclusionsOur review supports the hypothesis that schizophrenia is a disorder of disrupted within and between-region brain connectivity, and points to specific whole-brain and regional MRI metrics that may provide useful intermediate phenotypes.

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

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