TY - JOUR
T1 - Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease
AU - Baillie, J. Kenneth
AU - Bretherick, Andrew
AU - Haley, Christopher S.
AU - Clohisey, Sara
AU - Gray, Alan
AU - Neyton, Lucile P. A.
AU - Barrett, Jeffrey
AU - Stahl, Eli A.
AU - Tenesa, Albert
AU - Andersson, Robin
AU - Brown, J. Ben
AU - Faulkner, Geoffrey J.
AU - Lizio, Marina
AU - Schaefer, Ulf
AU - Daub, Carsten
AU - Itoh, Masayoshi
AU - Kondo, Naoto
AU - Lassmann, Timo
AU - Kawai, Jun
AU - Mole, Damian
AU - Bajic, Vladimir B.
AU - Heutink, Peter
AU - Rehli, Michael
AU - Kawaji, Hideya
AU - Sandelin, Albin Gustav
AU - Suzuki, Harukazu
AU - Satsangi, Jack
AU - Wells, Christine A.
AU - Hacohen, Nir
AU - Freeman, Thomas C.
AU - Hayashizaki, Yoshihide
AU - Carninci, Piero
AU - Forrest, Alistair R. R.
AU - Hume, David A.
PY - 2018/3
Y1 - 2018/3
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 similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.
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 similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.
U2 - 10.1371/journal.pcbi.1005934
DO - 10.1371/journal.pcbi.1005934
M3 - Journal article
C2 - 29494619
SN - 1553-7358
VL - 14
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 3
M1 - e1005934
ER -