De novo discovery of traits co-occurring with chronic obstructive pulmonary disease

Abstract

Epidemiological research indicates that chronic obstructive pulmonary disease (COPD) is a heterogeneous group of chronic lung conditions that are typically accompanied by cardiovascular disease, depression, lung cancer and other conditions. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with COPD and the co-occuring conditions, suggesting common biological mechanisms underlying COPD and these co-occuring conditions. To identify them, we have integrated information across different biological levels (i.e. genetic variants, lung-specific 3D genome structure, gene expression and protein-protein interactions) to build lung-specific gene regulatory and protein-protein interaction networks. We have queried these networks using disease-associated SNPs for COPD, unipolar depression and coronary artery disease. Our results show that COPD-associated SNPs can control genes involved in the regulation of lung or pulmonary function, asthma, brain region volumes, cortical surface area, depressed affect, neuroticism, Parkinson’s disease, white matter microstructure and smoking behaviour. We describe the regulatory connections, genes and biochemical pathways that underly these co-occuring trait-SNP-gene associations. Collectively, our findings provide new avenues for the investigation of the underlying biology and diverse clinical presentations of COPD. In so doing, we identify a collection of genetic variants and genes that may aid COPD patient stratification and treatment.

De novo identification of complex traits associated with asthma

“…The resulting lung GRN comprises 873,133 spatial eQTL-gene interactions (740,028 spatial eQTLs regulating 15,855 genes expressed in the lung) and has more cis-acting (eQTL-gene are separated by <1Mb) than trans-intrachromosomal (eQTL-gene pair are separated by ≥1Mb on the same chromosome) or trans-interchromosomal spatial eQTLs (eQTL-gene pair are located on different chromosomes). The lung GRN has been previously described in more detail (33). The whole blood GRN comprises 1,713,885 spatial eQTLs-gene interactions (1,077,379 spatial eQTLs regulating 14,871 genes expressed in whole blood).…”

“…These include venous thromboembolism (hazard ratio (HR): 3.24, (50)), amyloid A serum levels (51), protein C levels (52), intracranial volume (53), white matter microstructure (mean diusivities) (54,55) and depressive symptoms (56). Notably, of the 80 traits enriched across levels 0-4, only 8 were identi ed when running this analysis using COPD-associated SNPs, despite the use of the same lung GRN suggesting disease-speci c results (33). Known asthma-associated traits identi ed using the asthma B-GRN included serum folate levels (OR=1.45, 95% CI 1.05-2.02, (57)), urinary potassium excretion (58,59), monocyte percentage of white cells (60,61), and body mass index (relative risk: 1.21, 95% CI 1.16-1.26, ( 62)).…”

De novo identification of complex traits associated with asthma

“…The resulting lung GRN comprises 873,133 spatial eQTL-gene interactions (740,028 spatial eQTLs regulating 15,855 genes expressed in the lung) and has more cis-acting (eQTL-gene are separated by<1Mb) than trans-intrachromosomal (eQTL-gene pair are separated by ≥1Mb on the same chromosome) or trans-interchromosomal spatial eQTLs (eQTL-gene pair are located on different chromosomes). The lung GRN has been previously described in more detail ( 35 ). The whole blood GRN comprises 1,713,885 spatial eQTLs-gene interactions (1,077,379 spatial eQTLs regulating 14,871 genes expressed in whole blood).…”

“…These include venous thromboembolism (hazard ratio (HR): 3.24, ( 52 )), amyloid A serum levels ( 53 ), protein C levels ( 54 ), intracranial volume ( 55 ), white matter microstructure (mean diusivities) ( 56 , 57 ) and depressive symptoms ( 58 ). Notably, of the 80 traits enriched across levels 0-4, only 8 were identified when running this analysis using COPD-associated SNPs, (i.e., white blood cell count, vitiligo, serum metabolite levels, atopic asthma, asthma (adult onset), cortical surface area [global PC1], urinary metabolite levels in chronic kidney disease and urinary metabolite ratios in chronic kidney disease), despite the use of the same lung GRN, suggesting disease-specific results ( 35 ). Of the 82 traits identified in the blood GRN, all had known associations with asthma, apart from 8 traits whose association with asthma is yet to be confirmed, i.e., primary biliary cholangitis, nephropathy, giant cell arteritis, parental longevity, systolic blood pressure x alcohol consumption interaction, ENKTL-N, high light scatter reticulocyte count and reticulocyte fraction of red cells traits.…”

“…use of the same lung GRN, suggesting disease-specific results (35). Of the 82 traits identified in the blood GRN, all had known associations with asthma, apart from 8 traits whose association with asthma is yet to be confirmed, i.e., primary biliary cholangitis, nephropathy, giant cell arteritis, parental longevity, systolic blood pressure x alcohol consumption interaction, ENKTL-N, high light scatter reticulocyte count and reticulocyte fraction of red cells traits.…”