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.

Figure 1.

Forest plots showing the top-ranked schizophrenia-associated differentially methylated positions (DMPs). Shown are data for 12 DMPs associated with schizophrenia at a highly stringent significance threshold (P < 1.66E-07) derived using permutations to estimate the nominal P-value for 5% family-wise error. Additional information on these DMPs is given in Table 2. Colour depicts a brain region in which the schizophrenia-association was identified: prefrontal cortex = blue, striatum = green, hippocampus = red, and cerebellum = yellow.

Figure 2.

Differentially methylated regions (DMRs) associated with schizophrenia. Shown in chromosomal order are DMRs (Šidák-corrected P < 0.05, number of probes ≥ 2) associated with schizophrenia identified in any of the four tissues. Effect sizes for individual probes within each DMR are also shown for the other three brain regions (blue = hypomethylation, red = hypermethylation). Further details for individual DMRs are provided in Table 3.

Figure 3.

Increased polygenic burden for schizophrenia is associated with altered DNA methylation. (A) Schizophrenia samples included in our study scored significantly higher on a polygenic risk score derived from a recent large collaborative GWAS of schizophrenia. (B) The top-ranked PRS-associated DMP was cg20640266 (annotated to ZNF618) in the cerebellum. (C) The top-ranked multi-region PRS-associated DMP was cg04910228 (annotated to the TSNAX-DISC1 locus).

Figure 4.

Differentially methylated regions (DMRs) associated with schizophrenia polygenic risk score (PRS). Shown in chromosomal order are DMRs (Šidák-corrected P < 0.05, number of probes ≥2) associated with schizophrenia PRS identified in any of the four brain regions. Effect sizes for individual probes within each DMR are also shown for the other three brain regions (blue = hypomethylation, red = hypermethylation). Further details for individual DMRs are provided in Table 5.