Genetics and Environment in Adult Respiratory, Allergic and Cardiac disease

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

To investigate the effects of genomic and other omic and environmental factors, and their interactions, on respiratory health in adults we have established several high-quality population resources. We have been working with the extramurally funded cohort, the Atherosclerosis Risk in Communities (ARIC) study to examine both genetic and environmental factors in adult respiratory health. The ARIC study is a cohort of 16,000 adults assembled from 1987-1989 in four US communities. ARIC has a wealth of detailed cardiovascular and respiratory phenotypes. We have used the genome wide association genotyping in ARIC to look for novel genes associated with pulmonary function and chronic obstructive pulmonary disease (COPD) in the setting of the CHARGE Consortium. In 2009, we formed a pulmonary function analysis group within the CHARGE consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology) which includes several other cohorts with genome wide association genotyping and pulmonary function data (PMID: 20010835). In our first CHARGE meta-analysis of pulmonary traits, we identified eight novel loci related to pulmonary function. All have now been replicated by other groups. We subsequently developed a collaborated with a European consortium (SpiroMeta) to expand our work. We have published joint consortium papers on pulmonary function (PMID: 21946350) and COPD (PMID: 22837378 ). Again, our findings have been widely replaced. In 2012 we published one of the first papers incorporating interaction into genome wide association studies (PMID: 23284291). In so doing we identified 3 additional novel loci for pulmonary function. We have also published longitudinal analysis of lung function (PMID: 24983941). We identified 6 novel loci for forced vital capacity, a phenotype that we had not examined in our earlier papers (PMID: 24929828). We have also published on the use of targeted sequencing of two of the novel loci that we identified in our first CHARGE publication - HTR4 and ADAM19 (PMID: 24951661) We also examined rare and common variants in relation to lung function in the CHARGE and SpiroMeta Consortium (PMID: 30175238 ). These results suggest that rare variants do not underlie the associations that we identified earlier. In the past year, we revisited all three pulmonary function traits using 1000 Genomes imputation in the first large multi-ethnic meta-analysis of pulmonary function within our CHARGE group. We identified over 50 novel loci, increasing the number of known loci by 50% (PMID: 30061609). We have also used novel methods to evaluate rare variants in relation to pulmonary function and consider environmental interactions with rare variants. To identify novel biomarkers for reduced lung function and COPD, we examined circulating metabolomics profiles in two different population based studies including individuals of both European and African ancestry. We identified metabolomics signatures of these pulmonary traits common across ancestral groups. Having led a widely cited effort in the CHARGE Epigenetics group that identified widespread effects of tobacco smoking on methylation in adults (PMID 27651444), we are leading an effort to examine in association of genome wide methylation with pulmonary function and COPD. We have also pointed out challenges in assessing whether epigenetic changes related to smoking are mediators of effects of smoking on pulmonary function or COPD (PMIDs 28234025, 31273037). We have also identified effects of air pollution on methylation in blood (PMID 30819252). We led a CHARGE epigenome wide association meta-analysis of pulmonary function (PMID: 35536696 ).