Biology subjects

Hellard, S. L.

Publications and source records attributed to Hellard, S. L..

3 recordsLinked to original sources

bioRxiv2019

Functional analysis of evolutionary human methylated regions in schizophrenia patients

BackgroundRecent studies have implicated variations in DNA methylation in the aetiology of schizophrenia. Genome-wide scans in both brain and blood report differential methylated regions (DMRs) and positions (DMPs) between patients with schizophrenia and healthy controls. Previously, we reported that DMRs where human specific methylation (hDMR) has occurred over evolutionary time are enriched for schizophrenia-associated markers (SCZ_hDMR). However, it is unknown whether these human specific DMRs show variable methylation in patients with schizophrenia. MethodsUsing publicly available data, we investigate if human specific DMRs that harbour genetic variants associated with schizophrenia are differentially methylated between cases and controls. ResultsWe find statistically significant (p < 1e-4) methylation difference in schizophrenia associated human specific DMRs (SCZ hDMR) between brain samples of cases and controls. However, we fail to find evidence of similar differences in methylation in blood samples. ConclusionRegions that are evolutionarily important for human species and that are associated with schizophrenia, also show difference in methylation variation in the brain in patients with schizophrenia.

genomics↗

bioRxiv2018

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

IntroductionThe persistence of schizophrenia in human populations separated by geography and time led to the evolutionary hypothesis that proposes schizophrenia as a by-product of the higher cognitive abilities of modern humans. To explore this hypothesis, we used here an evolutionary epigenetics approach building on differentially methylated regions (DMRs) of the genome.\n\nMethodsWe implemented a polygenic enrichment testing pipeline using the summary statistics of genome-wide association studies (GWAS) of schizophrenia and 12 other phenotypes. We investigated the enrichment of association of these traits across genomic regions with variable methylation between modern humans and great apes (orangutans, chimpanzees and gorillas; primate DMRs) and between modern humans and recently extinct hominids (Neanderthals and Denisovans; non-primate DMRs).\n\nResultsRegions that are hypo-methylated in humans compared to great apes show enrichment of association with schizophrenia only if the major histocompatibility complex (MHC) region is included. With the MHC region removed from the analysis, only a modest enrichment for SNPs of low effect persists. The INRICH pipeline confirms this finding after rigorous permutation and bootstrapping procedures.\n\nConclusionThe analyses of regions with differential methylation changes in humans and great apes do not provide compelling evidence of enrichment of association with schizophrenia, in contrast to our previous findings on more recent methylation differences between modern humans, Neanderthals and Denisovans. Our results further support the evolutionary hypothesis of schizophrenia and indicate that the origin of some of the genetic susceptibility factors of schizophrenia may lie in recent human evolution.

genomics↗

bioRxiv2017

Human-specific methylated regions are enriched in schizophrenia

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.\n\nResultsSchizophrenia 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=5,000) in INRICH (p<0.01). Some enrichment of association with height was observed at the gene level.\n\nConclusionsRegions 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.

genetics↗