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 ...
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.