New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

“…Large enrichment, defined as the proportion of heritability accounted for by a specific category relative to the proportion of SNPs in that category, was observed for elements conserved in primates 19,20 (17.6% of SNPs, 54.7-58.5% of hg), McVicker background selection statistic 21,22 (17.8% of SNPs, 22.6-25.1% of hg), flanking bivalent transcription starting sites (TSS)/enhancers from Roadmap 20,23 (1.4% of SNPs, 11.1-13.2% of hg), and super enhancers (16.7% of SNPs, 33.9-38.6% of hg). We also replicated previously reported significant enrichments for histone methylation and acetylation marks H3K4me1, H3K9Ac, and H3K27Ac 18,24 .…”

“…As our understanding of the shared genetic and molecular pathways between lung cancer and pulmonary disease continues to evolve, identification of new susceptibility loci for pulmonary function and lung cancer risk may have important implications for future precision prevention and screening endeavors. Multiple genetic determinants of lung function are in pathways that contain druggable targets, based on our pQTL findings and previous reports 18 , which may open new avenues for chemoprevention or targeted therapies for lung cancers with an obstructive pulmonary etiology. In addition, with accumulating evidence supporting the effectiveness of low-dose computed tomography for lung cancer 62,63 , impairment in FEV1 and FEV1/FVC and their genetic determinants may provide additional information for refining risk-stratification and screening eligibility criteria.…”

“…After removing overlapping instruments between pulmonary phenotypes and LD-filtering (r 2 <0.05) across the three traits, 447 of the 601 variants were associated with at least one of FEV1, FVC, or FEV1/FVC (P<5´10 -8 , replication P<0.05). We compared these 447 independent variants to the 279 lung function variants recently reported by Shrine et al 18 based on an analysis of the UK Biobank and SpiroMeta consortium, by performing clumping with respect to these index variants (LD r 2 <0.05 within 10,000 kb). Our set of instruments included an additional 73 independent variants, 69 outside the MHC region (Supplementary Table 5), that achieved replication at the Bonferroni-corrected threshold for each trait (maximum replication P = 2.0´10 -4 ).…”

“…Partitioning heritability by functional annotation identified large and statistically significant (p<8.5´10 -4 ) enrichments for multiple categories (Figure 1; Supplementary Tables 1-3). A total of 35 categories, corresponding to 22 distinct annotations, were significantly enriched for all three pulmonary phenotypes, including annotations that were not previously reported 18 . Large enrichment, defined as the proportion of heritability accounted for by a specific category relative to the proportion of SNPs in that category, was observed for elements conserved in primates 19,20 (17.6% of SNPs, 54.7-58.5% of hg), McVicker background selection statistic 21,22 (17.8% of SNPs, 22.6-25.1% of hg), flanking bivalent transcription starting sites (TSS)/enhancers from Roadmap 20,23 (1.4% of SNPs, 11.1-13.2% of hg), and super enhancers (16.7% of SNPs, 33.9-38.6% of hg).…”

Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

“…41 The association between snoring genes and heel bone mineral density could be mediated by BMI due to the association between BMI and bone density documented previously. 42 MSRB3 plays a relevant role in protein and lipid metabolism pathways 43 and has been associated with hippocampal volume, [44][45][46] lung function, 40,47,48 Alzheimer's disease, 49,50 brain injuries, 51 novelty seeking, 52 deafness 53 and height. 40 These results could be consistent with the fact that severe snoring may incur in nocturnal oxygen desaturation, 54 diminishing neuropsychological functions and in some cases, resulting in tissue damage 55 and contributing to impairment of memory consolidation processes.…”