Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood (n = 6454) and lung (n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank-derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.
Peter Orchard, T. Blackwell, L. Kachuri et al.· Science· 0 citations
Chronic Obstructive Pulmonary disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are chronic pulmonary disorders with distinct pathologies but shared risk factors. Metabolomics may provide insights into mechanisms. To identify metabolites associated with COPD and IPF, and to characterize shared and disease-specific signatures. Plasma metabolomic profiling was conducted in the Lung Tissue Research Consortium (LTRC). Logistic regression identified metabolites associated with COPD and IPF, and results were replicated in an external cohort, COPDGene. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore disease-associated metabolite modules. We further evaluated relationships between significant metabolites and risk genes of interest. Of 1131 metabolites in LTRC, 246 (21.8%) differed between COPD and controls, and 136 (12.0%) between IPF and controls (FDR < 0.05). Among 80 shared significant metabolites in COPD and IPF, 77 showed concordant directions of effect. Shared metabolomic changes included reduced levels of steroids, triglycerides, diglycerides, phosphatidylcholines, and increased levels of carnitines. In contrast, polyunsaturated fatty acids, nicotine, and thyroxine metabolites differed between COPD and IPF; these findings were further explored by the WGCNA. External replication was performed for 120 metabolites measured in both cohorts, of which 49 (40.8%) replicated in COPD vs. control. In exploratory analyses leveraging quantitative imaging abnormalities (QIA) as a surrogate for IPF; only 4 (3.3%) metabolites replicated in the QIA vs. control model, and only 9 (7.5%) for COPD vs. QIA. Alterations in metabolomic profiles of COPD and IPF suggested shared dysregulation of several lipids. However, some metabolites pointed to disease-specific differences.
Aldric Rosario, N. Prince, S. Madha-Krause et al.· Metabolomics· 0 citations
