@article {Baillie095349, author = {J. Kenneth Baillie and Andrew Bretherick and Christopher S. Haley and Sara Clohisey and Alan Gray and Jeffrey Barret and Eli A. Stahl and Albert Tenesa and Robin Andersson and J. Ben Brown and Geoffrey J. Faulkner and Marina Lizio and Ulf Schaefer and Carsten Daub and Masayoshi Itoh and Naoto Kondo and Timo Lassmann and Jun Kawai and IIBDGC Consortium and FANTOM5 Consortium and Vladimir B. Bajic and Peter Heutink and Michael Rehli and Hideya Kawaji and Albin Sandelin and Harukazu Suzuki and Jack Satsangi and Christine A. Wells and Nir Hacohen and Thomas C Freeman and Yoshihide Hayashizaki and Piero Carninci and Alistair R.R. Forrest and David A. Hume}, title = {Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease}, elocation-id = {095349}, year = {2016}, doi = {10.1101/095349}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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{\textquoteright}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.}, URL = {https://www.biorxiv.org/content/early/2016/12/20/095349}, eprint = {https://www.biorxiv.org/content/early/2016/12/20/095349.full.pdf}, journal = {bioRxiv} }