Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Annah B. Wyss; Tamar Sofer; Mi Kyeong Lee; Natalie Terzikhan; Jennifer N. Nguyen; Lies Lahousse; Jeanne C. Latourelle; Albert Vernon Smith; Traci M. Bartz; Mary F. Feitosa; Wei Gao; Tarunveer S. Ahluwalia; Wenbo Tang; Christopher Oldmeadow; Qing Duan; Kim de Jong; Mary K. Wojczynski; Xin Qun Wang; Raymond Noordam; Fernando Pires Hartwig; Victoria E. Jackson; Tianyuan Wang; Ma’en Obeidat; Brian D. Hobbs; Tianxiao Huan; Hongsheng Gui; Margaret M. Parker; Donglei Hu; Lauren S. Mogil; Gleb Kichaev; Jianping Jin; Mariaelisa Graff; Tamara B. Harris; Ravi Kalhan; Susan R. Heckbert; Lavinia Paternoster; Kristin M. Burkart; Yongmei Liu; Elizabeth G. Holliday; James G. Wilson; Judith M. Vonk; Jason L. Sanders; R. Graham Barr; Renée de Mutsert; Ana Maria Baptista Menezes; Hieab H.H. Adams; Maarten van den Berge; Roby Joehanes; Albert M. Levin; Jennifer Liberto; Lenore J. Launer; Alanna C. Morrison; Colleen M. Sitlani; Juan C. Celedón; Stephen B. Kritchevsky; Rodney J. Scott; Kaare Christensen; Jerome I. Rotter; Tobias N. Bonten; Fernando César Wehrmeister; Yohan Bossé; Shujie Xiao; Sam Oh; Nora Franceschini; Jennifer A. Brody; Robert C. Kaplan; Kurt Lohman; Mark McEvoy; Michael A. Province; Frits R. Rosendaal; Kent D. Taylor; David C. Nickle; L. Keoki Williams; Esteban G. Burchard; Heather E. Wheeler; Don D. Sin; Vilmundur Gudnason; Kari E. North; Myriam Fornage; Bruce M. Psaty; Richard H. Myers; George O’Connor; Torben Hansen; Cathy C. Laurie; Patricia A. Cassano; Joohon Sung; Woo Jin Kim; John R. Attia; Leslie Lange; H. Marike Boezen; Bharat Thyagarajan; Stephen S. Rich; Dennis O. Mook-Kanamori; Bernardo Lessa Horta; André G. Uitterlinden; Hae Kyung Im; Michael H. Cho; Guy G. Brusselle; Sina A. Gharib; Josée Dupuis; Ani Manichaikul; Stephanie J. London

doi:10.1038/s41467-018-05369-0

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Annah B. Wyss, Tamar Sofer, Mi Kyeong Lee, Natalie Terzikhan, Jennifer N. Nguyen, Lies Lahousse, Jeanne C. Latourelle, Albert Vernon Smith, Traci M. Bartz, Mary F. Feitosa, Wei Gao, Tarunveer S. Ahluwalia, Wenbo Tang, Christopher Oldmeadow, Qing Duan, Kim de Jong, Mary K. Wojczynski, Xin Qun Wang, Raymond Noordam, Fernando Pires HartwigVictoria E. Jackson, Tianyuan Wang, Ma’en Obeidat, Brian D. Hobbs, Tianxiao Huan, Hongsheng Gui, Margaret M. Parker, Donglei Hu, Lauren S. Mogil, Gleb Kichaev, Jianping Jin, Mariaelisa Graff, Tamara B. Harris, Ravi Kalhan, Susan R. Heckbert, Lavinia Paternoster, Kristin M. Burkart, Yongmei Liu, Elizabeth G. Holliday, James G. Wilson, Judith M. Vonk, Jason L. Sanders, R. Graham Barr, Renée de Mutsert, Ana Maria Baptista Menezes, Hieab H.H. Adams, Maarten van den Berge, Roby Joehanes, Albert M. Levin, Jennifer Liberto, Lenore J. Launer, Alanna C. Morrison, Colleen M. Sitlani, Juan C. Celedón, Stephen B. Kritchevsky, Rodney J. Scott, Kaare Christensen, Jerome I. Rotter, Tobias N. Bonten, Fernando César Wehrmeister, Yohan Bossé, Shujie Xiao, Sam Oh, Nora Franceschini, Jennifer A. Brody, Robert C. Kaplan, Kurt Lohman, Mark McEvoy, Michael A. Province, Frits R. Rosendaal, Kent D. Taylor, David C. Nickle, L. Keoki Williams, Esteban G. Burchard, Heather E. Wheeler, Don D. Sin, Vilmundur Gudnason, Kari E. North, Myriam Fornage, Bruce M. Psaty, Richard H. Myers, George O’Connor, Torben Hansen, Cathy C. Laurie, Patricia A. Cassano, Joohon Sung, Woo Jin Kim, John R. Attia, Leslie Lange, H. Marike Boezen, Bharat Thyagarajan, Stephen S. Rich, Dennis O. Mook-Kanamori, Bernardo Lessa Horta, André G. Uitterlinden, Hae Kyung Im, Michael H. Cho, Guy G. Brusselle, Sina A. Gharib, Josée Dupuis, Ani Manichaikul, Stephanie J. London^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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	https://doi.org/10.1038/s41467-018-05369-0
State	Published - Dec 1 2018

Funding

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. 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.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wyss, A. B., Sofer, T., Lee, M. K., Terzikhan, N., Nguyen, J. N., Lahousse, L., Latourelle, J. C., Smith, A. V., Bartz, T. M., Feitosa, M. F., Gao, W., Ahluwalia, T. S., Tang, W., Oldmeadow, C., Duan, Q., de Jong, K., Wojczynski, M. K., Wang, X. Q., Noordam, R., ... London, S. J. (2018). Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nature communications, 9(1), Article 2976. https://doi.org/10.1038/s41467-018-05369-0

@article{f793e8ce516a479c818bd9df00f5b92d,

title = "Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function",

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.",

author = "Wyss, {Annah B.} and Tamar Sofer and Lee, {Mi Kyeong} and Natalie Terzikhan and Nguyen, {Jennifer N.} and Lies Lahousse and Latourelle, {Jeanne C.} and Smith, {Albert Vernon} and Bartz, {Traci M.} and Feitosa, {Mary F.} and Wei Gao and Ahluwalia, {Tarunveer S.} and Wenbo Tang and Christopher Oldmeadow and Qing Duan and {de Jong}, Kim and Wojczynski, {Mary K.} and Wang, {Xin Qun} and Raymond Noordam and Hartwig, {Fernando Pires} and Jackson, {Victoria E.} and Tianyuan Wang and Ma{\textquoteright}en Obeidat and Hobbs, {Brian D.} and Tianxiao Huan and Hongsheng Gui and Parker, {Margaret M.} and Donglei Hu and Mogil, {Lauren S.} and Gleb Kichaev and Jianping Jin and Mariaelisa Graff and Harris, {Tamara B.} and Ravi Kalhan and Heckbert, {Susan R.} and Lavinia Paternoster and Burkart, {Kristin M.} and Yongmei Liu and Holliday, {Elizabeth G.} and Wilson, {James G.} and Vonk, {Judith M.} and Sanders, {Jason L.} and Barr, {R. Graham} and {de Mutsert}, Ren{\'e}e and Menezes, {Ana Maria Baptista} and Adams, {Hieab H.H.} and {van den Berge}, Maarten and Roby Joehanes and Levin, {Albert M.} and Jennifer Liberto and Launer, {Lenore J.} and Morrison, {Alanna C.} and Sitlani, {Colleen M.} and Celed{\'o}n, {Juan C.} and Kritchevsky, {Stephen B.} and Scott, {Rodney J.} and Kaare Christensen and Rotter, {Jerome I.} and Bonten, {Tobias N.} and Wehrmeister, {Fernando C{\'e}sar} and Yohan Boss{\'e} and Shujie Xiao and Sam Oh and Nora Franceschini and Brody, {Jennifer A.} and Kaplan, {Robert C.} and Kurt Lohman and Mark McEvoy and Province, {Michael A.} and Rosendaal, {Frits R.} and Taylor, {Kent D.} and Nickle, {David C.} and Williams, {L. Keoki} and Burchard, {Esteban G.} and Wheeler, {Heather E.} and Sin, {Don D.} and Vilmundur Gudnason and North, {Kari E.} and Myriam Fornage and Psaty, {Bruce M.} and Myers, {Richard H.} and George O{\textquoteright}Connor and Torben Hansen and Laurie, {Cathy C.} and Cassano, {Patricia A.} and Joohon Sung and Kim, {Woo Jin} and Attia, {John R.} and Leslie Lange and Boezen, {H. Marike} and Bharat Thyagarajan and Rich, {Stephen S.} and Mook-Kanamori, {Dennis O.} and Horta, {Bernardo Lessa} and Uitterlinden, {Andr{\'e} G.} and Im, {Hae Kyung} and Cho, {Michael H.} and Brusselle, {Guy G.} and Gharib, {Sina A.} and Jos{\'e}e Dupuis and Ani Manichaikul and London, {Stephanie J.}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05369-0",

language = "English (US)",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

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Wyss, AB, Sofer, T, Lee, MK, Terzikhan, N, Nguyen, JN, Lahousse, L, Latourelle, JC, Smith, AV, Bartz, TM, Feitosa, MF, Gao, W, Ahluwalia, TS, Tang, W, Oldmeadow, C, Duan, Q, de Jong, K, Wojczynski, MK, Wang, XQ, Noordam, R, Hartwig, FP, Jackson, VE, Wang, T, Obeidat, M, Hobbs, BD, Huan, T, Gui, H, Parker, MM, Hu, D, Mogil, LS, Kichaev, G, Jin, J, Graff, M, Harris, TB, Kalhan, R, Heckbert, SR, Paternoster, L, Burkart, KM, Liu, Y, Holliday, EG, Wilson, JG, Vonk, JM, Sanders, JL, Barr, RG, de Mutsert, R, Menezes, AMB, Adams, HHH, van den Berge, M, Joehanes, R, Levin, AM, Liberto, J, Launer, LJ, Morrison, AC, Sitlani, CM, Celedón, JC, Kritchevsky, SB, Scott, RJ, Christensen, K, Rotter, JI, Bonten, TN, Wehrmeister, FC, Bossé, Y, Xiao, S, Oh, S, Franceschini, N, Brody, JA, Kaplan, RC, Lohman, K, McEvoy, M, Province, MA, Rosendaal, FR, Taylor, KD, Nickle, DC, Williams, LK, Burchard, EG, Wheeler, HE, Sin, DD, Gudnason, V, North, KE, Fornage, M, Psaty, BM, Myers, RH, O’Connor, G, Hansen, T, Laurie, CC, Cassano, PA, Sung, J, Kim, WJ, Attia, JR, Lange, L, Boezen, HM, Thyagarajan, B, Rich, SS, Mook-Kanamori, DO, Horta, BL, Uitterlinden, AG, Im, HK, Cho, MH, Brusselle, GG, Gharib, SA, Dupuis, J, Manichaikul, A & London, SJ 2018, 'Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function', Nature communications, vol. 9, no. 1, 2976. https://doi.org/10.1038/s41467-018-05369-0

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.

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

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2976

ER -

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

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