Abstract
Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
| Original language | English (US) |
|---|---|
| Article number | 2976 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. / Wyss, Annah B.; Sofer, Tamar; Lee, Mi Kyeong; Terzikhan, Natalie; Nguyen, Jennifer N.; Lahousse, Lies; Latourelle, Jeanne C.; Smith, Albert Vernon; Bartz, Traci M.; Feitosa, Mary F.; Gao, Wei; Ahluwalia, Tarunveer S.; Tang, Wenbo; Oldmeadow, Christopher; Duan, Qing; de Jong, Kim; Wojczynski, Mary K.; Wang, Xin Qun; Noordam, Raymond; Hartwig, Fernando Pires; Jackson, Victoria E.; Wang, Tianyuan; Obeidat, Ma’en; Hobbs, Brian D.; Huan, Tianxiao; Gui, Hongsheng; Parker, Margaret M.; Hu, Donglei; Mogil, Lauren S.; Kichaev, Gleb; Jin, Jianping; Graff, Mariaelisa; Harris, Tamara B.; Kalhan, Ravi; Heckbert, Susan R.; Paternoster, Lavinia; Burkart, Kristin M.; Liu, Yongmei; Holliday, Elizabeth G.; Wilson, James G.; Vonk, Judith M.; Sanders, Jason L.; Barr, R. Graham; de Mutsert, Renée; Menezes, Ana Maria Baptista; Adams, Hieab H.H.; van den Berge, Maarten; Joehanes, Roby; Levin, Albert M.; Liberto, Jennifer; Launer, Lenore J.; Morrison, Alanna C.; Sitlani, Colleen M.; Celedón, Juan C.; Kritchevsky, Stephen B.; Scott, Rodney J.; Christensen, Kaare; Rotter, Jerome I.; Bonten, Tobias N.; Wehrmeister, Fernando César; Bossé, Yohan; Xiao, Shujie; Oh, Sam; Franceschini, Nora; Brody, Jennifer A.; Kaplan, Robert C.; Lohman, Kurt; McEvoy, Mark; Province, Michael A.; Rosendaal, Frits R.; Taylor, Kent D.; Nickle, David C.; Williams, L. Keoki; Burchard, Esteban G.; Wheeler, Heather E.; Sin, Don D.; Gudnason, Vilmundur; North, Kari E.; Fornage, Myriam; Psaty, Bruce M.; Myers, Richard H.; O’Connor, George; Hansen, Torben; Laurie, Cathy C.; Cassano, Patricia A.; Sung, Joohon; Kim, Woo Jin; Attia, John R.; Lange, Leslie; Boezen, H. Marike; Thyagarajan, Bharat; Rich, Stephen S.; Mook-Kanamori, Dennis O.; Horta, Bernardo Lessa; Uitterlinden, André G.; Im, Hae Kyung; Cho, Michael H.; Brusselle, Guy G.; Gharib, Sina A.; Dupuis, Josée; Manichaikul, Ani; London, Stephanie J.
In: Nature communications, Vol. 9, No. 1, 2976, 01.12.2018.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function
AU - Wyss, Annah B.
AU - Sofer, Tamar
AU - Lee, Mi Kyeong
AU - Terzikhan, Natalie
AU - Nguyen, Jennifer N.
AU - Lahousse, Lies
AU - Latourelle, Jeanne C.
AU - Smith, Albert Vernon
AU - Bartz, Traci M.
AU - Feitosa, Mary F.
AU - Gao, Wei
AU - Ahluwalia, Tarunveer S.
AU - Tang, Wenbo
AU - Oldmeadow, Christopher
AU - Duan, Qing
AU - de Jong, Kim
AU - Wojczynski, Mary K.
AU - Wang, Xin Qun
AU - Noordam, Raymond
AU - Hartwig, Fernando Pires
AU - Jackson, Victoria E.
AU - Wang, Tianyuan
AU - Obeidat, Ma’en
AU - Hobbs, Brian D.
AU - Huan, Tianxiao
AU - Gui, Hongsheng
AU - Parker, Margaret M.
AU - Hu, Donglei
AU - Mogil, Lauren S.
AU - Kichaev, Gleb
AU - Jin, Jianping
AU - Graff, Mariaelisa
AU - Harris, Tamara B.
AU - Kalhan, Ravi
AU - Heckbert, Susan R.
AU - Paternoster, Lavinia
AU - Burkart, Kristin M.
AU - Liu, Yongmei
AU - Holliday, Elizabeth G.
AU - Wilson, James G.
AU - Vonk, Judith M.
AU - Sanders, Jason L.
AU - Barr, R. Graham
AU - de Mutsert, Renée
AU - Menezes, Ana Maria Baptista
AU - Adams, Hieab H.H.
AU - van den Berge, Maarten
AU - Joehanes, Roby
AU - Levin, Albert M.
AU - Liberto, Jennifer
AU - Launer, Lenore J.
AU - Morrison, Alanna C.
AU - Sitlani, Colleen M.
AU - Celedón, Juan C.
AU - Kritchevsky, Stephen B.
AU - Scott, Rodney J.
AU - Christensen, Kaare
AU - Rotter, Jerome I.
AU - Bonten, Tobias N.
AU - Wehrmeister, Fernando César
AU - Bossé, Yohan
AU - Xiao, Shujie
AU - Oh, Sam
AU - Franceschini, Nora
AU - Brody, Jennifer A.
AU - Kaplan, Robert C.
AU - Lohman, Kurt
AU - McEvoy, Mark
AU - Province, Michael A.
AU - Rosendaal, Frits R.
AU - Taylor, Kent D.
AU - Nickle, David C.
AU - Williams, L. Keoki
AU - Burchard, Esteban G.
AU - Wheeler, Heather E.
AU - Sin, Don D.
AU - Gudnason, Vilmundur
AU - North, Kari E.
AU - Fornage, Myriam
AU - Psaty, Bruce M.
AU - Myers, Richard H.
AU - O’Connor, George
AU - Hansen, Torben
AU - Laurie, Cathy C.
AU - Cassano, Patricia A.
AU - Sung, Joohon
AU - Kim, Woo Jin
AU - Attia, John R.
AU - Lange, Leslie
AU - Boezen, H. Marike
AU - Thyagarajan, Bharat
AU - Rich, Stephen S.
AU - Mook-Kanamori, Dennis O.
AU - Horta, Bernardo Lessa
AU - Uitterlinden, André G.
AU - Im, Hae Kyung
AU - Cho, Michael H.
AU - Brusselle, Guy G.
AU - Gharib, Sina A.
AU - Dupuis, Josée
AU - Manichaikul, Ani
AU - London, Stephanie J.
N1 - Funding Information: We thank the International COPD Genetics Consortium (members listed in Supplementary Note 3) for investigating overlap of newly identified lung function loci with COPD in their study. We also thank Huiling Li for expert technical assistance and Dr. Frank Day for computational support, both from the National Institute of Environmental Health Sciences (NIEHS), and Dr. Louise Wain, University of Leicester, for critical reviews of the manuscript. Supported in part by the Intramural Research Program of the National Institutes of Health, NIEHS. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant R01HL105756. Study-specific funding and acknowledgments can be found in Supplementary Note 3. Funding Information: Competing interests: J.C.L. is currently an employee of GNS Healthcare. W.T. is currently an employee of Boehringer Ingelheim Pharmaceuticals. A.M.B.M. has received grant support from GlaxoSmithKline and from AstraZeneca in the last 5 years, but not for the present study. J.C.C. received research materials from Pharmavite (vitamin D and placebo capsules), GSK (Flovent), and Merck (Asmanex) to provide medications free of cost to participants in NIH-funded studies. D.C.N. is an employee of Merck Research Laboratories. D.D.S. has received research funding from Boehringer Ingelheim, Merck, and AstraZeneca outside the scope of this work. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.H.C. has received grant support from GlaxoSmithKline. The authors declare no other competing interests. Publisher Copyright: © 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
AB - Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
UR - http://www.scopus.com/inward/record.url?scp=85050820503&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050820503&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05369-0
DO - 10.1038/s41467-018-05369-0
M3 - Article
C2 - 30061609
AN - SCOPUS:85050820503
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2976
ER -