PT  - JOURNAL ARTICLE
AU  - Wilson Lek Wen Tan
AU  - Chukwuemeka George Anene-Nzelu
AU  - Eleanor Wong
AU  - Hui San Tan
AU  - Pan Bangfen
AU  - Chang Jie Mick Lee
AU  - Matias Ilmari Autio
AU  - Michael P. Morley
AU  - Kenneth B. Margulies
AU  - Thomas P. Cappola
AU  - Marie Loh
AU  - John Chambers
AU  - Shyam Prabhakar
AU  - Roger Foo
TI  - Disease and phenotype relevant genetic variants identified from histone acetylomes in human hearts
AID  - 10.1101/536763
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 536763
4099  - http://biorxiv.org/content/early/2019/01/31/536763.short
4100  - http://biorxiv.org/content/early/2019/01/31/536763.full
AB  - Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to demonstrate statistical significance1. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR < 0.05) pointed to recognizable pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test2 to call out 1,680 haQTLs (FDR < 0.1). A subset of these showed significant association to gene expression, either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. Furthermore, a concordant relationship was found between the gain or disruption of specific transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, associated with altered H3K27ac peak heights. Finally, colocalisation of our haQTLs with heart-related GWAS datasets allowed us to identify 62 unique loci. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.