Human-specific methylated regions are enriched in schizophrenia

Abstract

Background: Despite the reduced fertility of patients, schizophrenia has a prevalence of ~1% in the general population. One explanation for this persistence is that schizophrenia is a by-product of human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. We tested if genetic variants located within human-specific differentially methylated regions (DMRs) are enriched for association with schizophrenia. Methods: We used analytical tools that evaluate the polygenic enrichment of a set of genomic variants against all genomic variants. SNPs identified in genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes were classified according to their location in previously defined human-specific DMRs. These DMR SNPs were then tested for enrichment of association with the GWAS trait. Results: Schizophrenia was the only trait in which GWAS SNPs within human-specific DMRs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. Conclusions: Regions where DNA methylation modifications have changed during recent human evolution harbor more schizophrenia-associated genetic variants than expected. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Our results also suggest that interaction with the environment might have contributed to that association.