4.4 Article

Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains

Journal

MOLECULAR BRAIN
Volume 12, Issue -, Pages -

Publisher

BMC
DOI: 10.1186/s13041-019-0429-4

Keywords

H3K27ac; Active enhancer; Promoter; GWAS; Brain disorder; LD score regression; Psychiatric illness; Neurodegenerative disease; Epigenetics

Categories

Funding

  1. US National Institutes of Health [R01 AG036039]
  2. UK Medical Research Council (MRC) [MR/R005176/1]
  3. EU-FP7 Marie Curie ITN EpiTrain (REA) [316758]
  4. Wellcome Trust Multi User Equipment Award [WT101650MA]
  5. Medical Research Council (MRC) Clinical Infrastructure Funding [MR/M008924/1]
  6. MRC [MR/M008924/1, MR/R005176/1] Funding Source: UKRI

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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 publicly-available 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.

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