RT Journal Article
SR Electronic
T1 Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 095349
DO 10.1101/095349
A1 J. Kenneth Baillie
A1 Andrew Bretherick
A1 Christopher S. Haley
A1 Sara Clohisey
A1 Alan Gray
A1 Jeffrey Barret
A1 Eli A. Stahl
A1 Albert Tenesa
A1 Robin Andersson
A1 J. Ben Brown
A1 Geoffrey J. Faulkner
A1 Marina Lizio
A1 Ulf Schaefer
A1 Carsten Daub
A1 Masayoshi Itoh
A1 Naoto Kondo
A1 Timo Lassmann
A1 Jun Kawai
A1 IIBDGC Consortium
A1 FANTOM5 Consortium
A1 Vladimir B. Bajic
A1 Peter Heutink
A1 Michael Rehli
A1 Hideya Kawaji
A1 Albin Sandelin
A1 Harukazu Suzuki
A1 Jack Satsangi
A1 Christine A. Wells
A1 Nir Hacohen
A1 Thomas C Freeman
A1 Yoshihide Hayashizaki
A1 Piero Carninci
A1 Alistair R.R. Forrest
A1 David A. Hume
YR 2016
UL http://biorxiv.org/content/early/2016/12/20/095349.abstract
AB 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.