Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• DNA methylation (DNAm) plays a crucial role in brain development.
• Aberrant DNAm patterns are implicated in the pathophysiology of schizophrenia.
• Understanding DNAm across the lifespan is key to deciphering neurodevelopmental disorders.

Purpose of the Study:

• To characterize DNA methylation patterns in the prefrontal cortex across the lifespan in controls and schizophrenia patients.
• To investigate the relationship between DNAm changes, cellular landscape shifts, and genetic risk for schizophrenia.
• To identify specific DNAm alterations associated with schizophrenia and their developmental timing.

Main Methods:

• Analysis of DNA methylation in prefrontal cortex samples from 335 non-psychiatric controls and 191 schizophrenia patients.
• Correlation of DNAm changes with transcriptome data and cellular composition.
• Integration of DNAm quantitative trait loci (meQTLs) with genome-wide association study (GWAS) data for schizophrenia risk loci.

Main Results:

• Widespread DNAm changes were observed during the prenatal to postnatal transition.
• DNAm alterations correlated with shifts in cellular landscape and overlapped with schizophrenia genetic risk regions.
• A significant proportion of GWAS-suggestive loci and schizophrenia GWAS-positive loci were identified as meQTLs.
• 2,104 differentially methylated CpGs were found in schizophrenia patients, enriched for developmental and neurodifferentiation genes.
• Schizophrenia-associated CpGs were linked to prenatal-postnatal transition changes, not adolescent-adult transitions.

Conclusions:

• Epigenetic dysregulation, particularly DNA methylation changes during early development, contributes to the developmental origins of schizophrenia.
• The identified DNAm patterns provide insights into the interplay between genetic predisposition and environmental factors in schizophrenia.
• These findings underscore the importance of studying epigenetic modifications in understanding complex psychiatric disorders.