Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains
dc.contributor.author | Hannon, E | |
dc.contributor.author | Marzi, SJ | |
dc.contributor.author | Schalkwyk, LS | |
dc.contributor.author | Mill, J | |
dc.date.accessioned | 2019-03-29T09:35:37Z | |
dc.date.issued | 2019-01-28 | |
dc.description.abstract | Most variants associated with complex phenotypes in genome-wide association studies (GWAS) do not directly index coding changes affecting protein structure. Instead they are hypothesized to influence gene regulation, with common variants associated with disease being enriched in regulatory domains including enhancers and regions of open chromatin. There is interest, therefore, in using epigenomic annotation data to identify the specific regulatory mechanisms involved and prioritize risk variants. We quantified lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding – across the genome in entorhinal cortex samples using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). H3K27ac peaks were called using high quality reads combined across all samples and formed the basis of partitioned heritability analysis using LD score regression along with publiclyavailable GWAS results for seven psychiatric and neurodegenerative traits. Heritability for all seven brain traits was significantly enriched in these H3K27ac peaks (enrichment ranging from 1.09–2.13) compared to regions of the genome containing other active regulatory and functional elements across multiple cell types and tissues. The strongest enrichments were for amyotrophic lateral sclerosis (ALS) (enrichment = 2.19; 95% CI = 2.12–2.27), autism (enrichment = 2.11; 95% CI = 2.05–2.16) and major depressive disorder (enrichment = 2.04; 95% CI = 1.92–2.16). Much lower enrichments were observed for 14 non-brain disorders, although we identified enrichment in cortical H3K27ac domains for body mass index (enrichment = 1.16; 95% CI = 1.13–1.19), ever smoked (enrichment = 2.07; 95% CI = 2.04–2.10), HDL (enrichment = 1.53; 95% CI = 1.45–1.62) and trigylcerides (enrichment = 1.33; 95% CI = 1.24–1.42). These results indicate that risk alleles for brain disorders are preferentially located in regions of regulatory/enhancer function in the cortex, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | National Institute for Health Research (NIHR) | en_GB |
dc.description.sponsorship | European Union: 7th Framework Programme | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.identifier.citation | Vol. 12:7 | en_GB |
dc.identifier.doi | 10.1186/s13041-019-0429-4 | |
dc.identifier.grantnumber | MR/R005176/1 | en_GB |
dc.identifier.grantnumber | R01 AG036039 | en_GB |
dc.identifier.grantnumber | 316758 | en_GB |
dc.identifier.grantnumber | WT101650MA | en_GB |
dc.identifier.grantnumber | MR/M008924/1 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/36666 | |
dc.language.iso | en | en_GB |
dc.publisher | BMC | en_GB |
dc.rights | © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | en_GB |
dc.subject | H3K27ac | en_GB |
dc.subject | Active enhancer | en_GB |
dc.subject | Promoter | en_GB |
dc.subject | GWAS | en_GB |
dc.subject | Brain disorder | en_GB |
dc.subject | LD score regression | en_GB |
dc.subject | Psychiatric illness | en_GB |
dc.subject | Neurodegenerative disease | en_GB |
dc.subject | Epigenetics | en_GB |
dc.title | Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-03-29T09:35:37Z | |
dc.identifier.issn | 1756-6606 | |
exeter.article-number | ARTN 7 | en_GB |
dc.description | H3K27ac ChIP-seq data has been deposited in GEO under accession number GSE102538. | en_GB |
dc.description | This is the final version. Available from the publisher via the DOI in this record. | en_GB |
dc.identifier.journal | Molecular brain | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-01-01 | |
exeter.funder | ::Medical Research Council (MRC) | en_GB |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-01-28 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-03-29T08:32:44Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2019-03-29T09:35:43Z | |
refterms.panel | A | en_GB |
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