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.

Variability of DNA Methylation within Schizophrenia Risk Loci across Subregions of Human Hippocampus

“…These data are consistent with another recently published study that investigated schizophrenia-associated DNA methylation changes across four distinct regions of the human brain in homogenized whole cortex, accounting for estimates of neuronal/glial proportions in each sample [20]. The prior study found multiple DMPositions and DMRegions between schizophrenia and control subjects, and while many were shared across brain regions, the majority of these changes were significant in only a subset of regions, with the cerebellum being the most distinct region assayed.…”

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

“…Previous studies that investigated DNAm aging in SCZ did not observe significant differential aging [27][28][29][30][31] , highlighting that sample size and/or explicit modeling of age-and sexdependent effects are crucial factors when investigating aging in SCZ. Our findings also demonstrate that analyzing these clocks simultaneously can reveal new insights that may otherwise be missed.…”

“…While different aging biomarkers have been studied, there is no clear demonstration of altered aging in SCZ 11 . More specifically, DNAm age predictors have found limited to no evidence for altered epigenetic aging in either brain or blood [27][28][29][30][31] . These studies, however, (i) consisted of small sample sizes and thus limiting the ability to detect a biological signal, (ii) used a single epigenetic clock that may have not been most informative for aging studies of psychiatric disorders, and (iii) did not consider aging differences across the life-span of patients.…”

Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches

“…Much of the work toward epigenetically characterizing the schizophrenia epigenome has involved measuring direct DNA methylation through bisulphite sequencing and similar methods. For example, a recent study (41 cases, 46 controls) across 4 brain regions found many genome regions that displayed differentially methylated DNA [28], while a larger study (689 cases, 645 controls) using blood samples similarly identified many differentially methylated loci [29]. Other studies support the importance of DNA cytosine methylation in schizophrenia [30-32].…”