Derivation of poly-methylomic profile scores for schizophrenia

Schizophrenia and bipolar disorder share biological features and environmental risk factors that may be associated with altered DNA methylation. In this study we sought to: 1) construct a novel ‘Poly-Methylomic Profile Score (PMPS)’ by transforming schizophrenia-associated epigenome-wide methylation from a previously published epigenome-wide association study (EWAS) into a single quantitative metric; and 2) examine associations between the PMPS and clinical status in an independent sample of 57 schizophrenia (SZ) cases, 59 bipolar disorder (BD) cases and 55 healthy controls (HC) for whom blood-derived DNA methylation was quantified using the Illumina 450 K methylation beadchip. We constructed five PMPSs at different p-value thresholds by summing methylation beta-values weighted by individual-CpG effect sizes from the meta-analysis of a previously published schizophrenia EWAS (comprising three separate cohorts with 675 [353 SZ and 322 HC] discovery cohort participants, 847 [414 SZ and 433 HC] replication cohort participants, and 96 monozygotic twin-pairs discordant for SZ). All SZ PMPSs were elevated in SZ participants relative to HCs, with the score calculated at a p-value threshold of 1 × 10⁻⁵ accounting for the greatest amount of variance. All PMPSs were elevated in SZ relative to BD and none of the PMPSs were increased in BD, or in a combined cohort of BD and SZ cases, relative to HCs. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated in SZ, but not BD, suggests that epigenome-wide methylation patterns may represent distinct pathophysiology that is yet to be elucidated.