Recently evolved human-specific methylated regions are enriched in schizophrenia signals

Area of Science:

• Evolutionary genetics
• Human evolution
• Neuroscience

Background:

• Schizophrenia persists despite reduced fertility, suggesting an evolutionary explanation.
• Recent human genomic regions are implicated in schizophrenia genetic risk.
• Human-specific differentially methylated regions (DMRs) arose from lineage-specific epigenetic changes.

Purpose of the Study:

• To investigate if human-specific DMRs are enriched for genetic associations with schizophrenia.
• To test for enrichment of schizophrenia GWAS traits in human-specific DMRs compared to Neanderthal/Denisovan DMRs.

Main Methods:

• Utilized summary statistics from genome-wide association studies (GWAS) for schizophrenia and 11 other traits.
• Applied analytical tools to evaluate polygenic enrichment of single nucleotide polymorphisms (SNPs) within DMRs.
• Compared enrichment in human-specific DMRs against Neanderthal and Denisovan DMRs.

Main Results:

• Schizophrenia showed significant enrichment of association with human-specific DMR SNPs, surpassing the genome-wide significance threshold.
• No significant enrichment was observed for Neanderthal or Denisovan DMRs.
• Enrichment in human DMRs was comparable to Neanderthal Selective Sweep markers and stronger than Human Accelerated Regions.

Conclusions:

• Genomic regions with altered DNA methylation during recent human evolution are associated with schizophrenia risk.
• This supports the hypothesis that schizophrenia risk variants are located in evolutionarily changed genomic regions.
• Epigenetic modifications and environmental interactions may contribute to schizophrenia's association with human evolution.