Schizophrenia is associated with altered DNA methylation variance

Area of Science:

• Psychiatric epigenetics
• Neuroscience
• Genetics

Background:

• Phenotypic heterogeneity in schizophrenia is influenced by genetic and environmental factors.
• Epigenome-wide association studies (EWAS) in schizophrenia reveal altered DNA methylation levels.
• DNA methylation variance, distinct from mean changes, is understudied but may explain individual differences.

Purpose of the Study:

• To investigate DNA methylation variance in schizophrenia using the largest meta-analysis to date.
• To determine the overlap between variably methylated positions (VMPs) and differentially methylated positions (DMPs).
• To explore the association of DNA methylation variance with clinical characteristics and brain regions.

Main Methods:

• Meta-analysis of blood DNA methylation variance across three cohorts (1036 schizophrenia cases, 954 controls).
• Analysis of variably methylated positions (VMPs) and differentially methylated positions (DMPs).
• Examination of VMP association with schizophrenia-related genes, brain-enriched genes, and clinical metrics.

Main Results:

• A small overlap (0.1%) was found between schizophrenia-associated VMPs and DMPs.
• Schizophrenia-associated VMPs were enriched in schizophrenia-related and brain-enriched genes.
• DNA methylation variance showed covariance with age of onset, cognitive deficits, and symptom severity.
• Significant VMPs were identified in first-episode psychosis cohorts.

Conclusions:

• Schizophrenia is associated with substantial changes in DNA methylation variance.
• DNA methylation variance may be a key contributor to phenotypic heterogeneity in schizophrenia.
• These findings highlight the importance of studying methylation variance for understanding schizophrenia.