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

Abstract

BackgroundOne explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.ResultsSchizophrenia was the only trait in which DMR SNPs 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. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level.ConclusionsRegions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. 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. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1177-2) contains supplementary material, which is available to authorized users.

Analysis of differentially methylated regions in primates and non-primates provides support for the evolutionary hypothesis of schizophrenia

“…As described in depth by Schork et al (2013), a leftward deflection of the observed distribution from the null line represents enrichment – the greater the leftward deflection, the stronger the enrichment of true signals. This method has been used recently not only to show how specific genomic annotation affects the distribution of disease SNPs with true signals (Schork et al, 2013), but also to demonstrate that regions of recent evolution are enriched for schizophrenia markers (Banerjee et al, 2017; Srinivasan et al, 2015). We took the SNPs that are in LD with the DMR regions and plotted their p -value distributions from various GWASs.…”

“…the DMRs were enriched for SCZ markers both at the single-nucleotide polymorphism (SNP) level and at the gene level. These human-specific DMRs thus provide evidence of enrichment of methylation changes in regions harbouring genetic variants associated with schizophrenia, at least since the divergence from Neanderthals and Denisovans (Banerjee et al, 2017).…”

“…They reported that while 97% of the methylome was comparable between humans, Neanderthals and Denisovans, some regions showed differential methylation between the three hominids. Previously (Banerjee et al, 2017), we analysed the differentially methylated regions (DMRs) identified for Neanderthals, Denisovans and modern humans by Gokhman et al (2014), and found evidence that the regions of the genome with human-specific DMRs harbour relatively more genetic variants associated with schizophrenia than the rest of the genome, i.e. the DMRs were enriched for SCZ markers both at the single-nucleotide polymorphism (SNP) level and at the gene level.…”

Functional analysis of evolutionary human methylated regions in schizophrenia patients

“…Although most of the methylated regions were similar between the three hominids, 2000 regions were differentially methylated amongst the three hominid species. Building up on their study, we found that the human specific differentially methylated regions (hDMRs) show an enrichment of genetic variants associated with schizophrenia (compared to the rest of the genome [24]). While regions differentially methylated between human and great apes [25] do not show such an enrichment.…”

“…We first determine an experiment-wide significance threshold to select the SNPs and DMRs. About 27,000 SNPs were located in or in linkage-disequilibrium (LD) with h_DMRs [24]. We followed the procedure of Moskvina et al [31] and estimated 2048 independent SNPs that with a Bonferroni correction at α = 0.05 gives an experiment-wide threshold of 2.46x10e-5.…”