Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell type and phenotype associations

Sakornsakolpat, Phuwanat; Prokopenko, Dmitry; Lamontagne, Maxime; Reeve, Nicola F.; Guyatt, Anna L.; Jackson, Victoria E.; Shrine, Nick; Qiao, Dandi; Bartz, Traci M.; Kim, Deog Kyeom; Lee, Mi Kyeong; Latourelle, Jeanne C.; Li, Xingnan; Morrow, Jarrett D.; Obeidat, Ma'en; Wyss, Annah B.; Bakke, Per; Graham Barr, R.; Beaty, Terri H.; Belinsky, Steven A.; Brusselle, Guy G.; Crapo, James D.; de Jong, Kim; DeMeo, Dawn L.; Fingerlin, Tasha L.; Gharib, Sina A.; Gulsvik, Amund; Hall, Ian P.; Hokanson, John E.; Jin Kim, Woo; Lomas, David A.; London, Stephanie J.; Meyers, Deborah A.; O'Connor, George T.; Rennard, Stephen I.; Schwartz, David A.; Sliwinski, Pawel; Sparrow, David; Strachan, David P.; Tal-Singer, Ruth; Tesfaigzi, Yohannes; Vestbo, J�rgen; Vonk, Judith M.; Yim, Jae-Joon; Zhou, Xiaobo; Bosse, Yohan; Manichaikul, Ani; Lahousse, Lies; Silverman, Edwin K.; Marike Boezen, H.; Wain, Louise V.; Tobin, Martin D.; Hobbs, Brian D.; Cho, Michael H.

Abstract

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P-value [less than] 5 × 10-8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

Citation

Sakornsakolpat, P., Prokopenko, D., Lamontagne, M., Reeve, N. F., Guyatt, A. L., Jackson, V. E., …Cho, M. H. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell type and phenotype associations. Nature Genetics, 51(3), 494–505. https://doi.org/10.1038/s41588-018-0342-2

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2018
• Online Publication Date: Feb 25, 2019
• Publication Date: 2019-03
• Deposit Date: Feb 20, 2019
• Publicly Available Date: Aug 26, 2019
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 51
• Issue: 3
• Pages: 494–505
• DOI: https://doi.org/10.1038/s41588-018-0342-2
• Public URL: https://nottingham-repository.worktribe.com/output/1568579
• Publisher URL: https://www.nature.com/articles/s41588-018-0342-2
• Additional Information: Additional authors: SpiroMeta Consortium, International COPD Genetics Consortium