TY - JOUR T1 - Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease JF - bioRxiv DO - 10.1101/095349 SP - 095349 AU - J. Kenneth Baillie AU - Andrew Bretherick AU - Christopher S. Haley AU - Sara Clohisey AU - Alan Gray AU - Jeffrey Barret AU - Eli A. Stahl AU - Albert Tenesa AU - Robin Andersson AU - J. Ben Brown AU - Geoffrey J. Faulkner AU - Marina Lizio AU - Ulf Schaefer AU - Carsten Daub AU - Masayoshi Itoh AU - Naoto Kondo AU - Timo Lassmann AU - Jun Kawai AU - IIBDGC Consortium AU - FANTOM5 Consortium AU - Vladimir B. Bajic AU - Peter Heutink AU - Michael Rehli AU - Hideya Kawaji AU - Albin Sandelin AU - Harukazu Suzuki AU - Jack Satsangi AU - Christine A. Wells AU - Nir Hacohen AU - Thomas C Freeman AU - Yoshihide Hayashizaki AU - Piero Carninci AU - Alistair R.R. Forrest AU - David A. Hume Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/12/19/095349.abstract N2 - Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share patterns of transcriptional regulation. Accordingly, shared transcriptional regulation (coexpression) may help prioritise loci associated with a given trait, and help to identify the biological processes underlying it. Using cap analysis of gene expression (CAGE) profiles of promoter-and enhancer-derived RNAs across 1824 human samples, we have quantified coexpression of RNAs originating from trait-associated regulatory regions using a novel analytical method (network density analysis; NDA). For most traits studied, sequence variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. These networks implicate particular cell types and tissues in disease pathogenesis; for example, variants associated with ulcerative colitis are linked to expression in gut tissue, whereas Crohn’s disease variants are restricted to immune cells. We show that this coexpression signal provides additional independent information for fine mapping likely causative variants. This approach identifies additional genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. This approach enables a deeper biological understanding of the causal basis of complex traits.ONE SENTENCE SUMMARY We discover that variants associated with a specific disease share expression profiles across tissues and cell types, enabling fine mapping and identification of new disease-associated variants, illuminating key cell types involved in disease pathogenesis. ER -