Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Lung Working Group

doi:10.1038/s41467-020-18334-7

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group

Epidemiology & Population Health

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

Abstract

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

Original language	English (US)
Article number	5182
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18334-7
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/s41467-020-18334-7

Fingerprint Dive into the research topics of 'Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants'. Together they form a unique fingerprint.

Cite this

@article{914be95c0bcf4e359dc573adb7f5f96b,

title = "Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants",

abstract = "Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.",

author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and {TOPMed Lung Working Group} and Xutong Zhao and Dandi Qiao and Chaojie Yang and Silva Kasela and Wonji Kim and Yanlin Ma and Nick Shrine and Chiara Batini and Tamar Sofer and Taliun, {Sarah A.Gagliano} and Phuwanat Sakornsakolpat and Balte, {Pallavi P.} and Dmitry Prokopenko and Bing Yu and Lange, {Leslie A.} and Jos{\'e}e Dupuis and Cade, {Brian E.} and Jiwon Lee and Gharib, {Sina A.} and Michelle Daya and Laurie, {Cecelia A.} and Ingo Ruczinski and Cupples, {L. Adrienne} and Loehr, {Laura R.} and Bartz, {Traci M.} and Morrison, {Alanna C.} and Psaty, {Bruce M.} and Vasan, {Ramachandran S.} and Wilson, {James G.} and Taylor, {Kent D.} and Peter Durda and Johnson, {W. Craig} and Elaine Cornell and Xiuqing Guo and Yongmei Liu and Tracy, {Russell P.} and Ardlie, {Kristin G.} and Fran{\c c}ois Aguet and VanDenBerg, {David J.} and Papanicolaou, {George J.} and Rotter, {Jerome I.} and Barnes, {Kathleen C.} and Deepti Jain and Nickerson, {Deborah A.} and Muzny, {Donna M.} and Metcalf, {Ginger A.} and Harshavardhan Doddapaneni and Shannon Dugan-Perez and Namrata Gupta and Kaplan, {Robert C.}",

note = "Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Atherosclerosis Risk in Communities (ARIC)” (phs001211) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2) and the Broad Institute for MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: Cardiovascular Health Study (CHS)” (phs001368) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C). WGS for “NHLBI TOPMed: The Cleveland Family Study” (phs000954) was performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Fra-mingham Heart Study” (phs000974) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C and 3R01HL092577-06S1). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1 and HHSN268201500014C). WGS for “NHLBI TOPMed: Boston Early-Onset COPD Study in the TOPMed Program” (phs000946) was performed at the University of Washington Northwest Genomics Center (3R01HL089856-08S1). WGS for “NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene) in the TOPMed Program” (phs000951) was performed at the University of Washington Northwest Genomics Center (3R01 HL089856-08S1) and the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The TOPMed MESA Multi-Omics project was conducted by the University of Washington and LABioMed (HHSN2682015000031/HHSN26800004). Phenotype harmonization for pulmonary traits was contributed by the NHLBI Pooled Cohorts Study with funding from NIH/NHLBI R21 HL121457, R21 HL129924, K23 HL130627, R01 HL077612. This research was supported by a TOPMed Analysis Support Award (through U01 HL117626), NIH/NHLBI R01 HL131565 (A.M.), R01 HL142028 (T.L.), R01 HL135142; R01 HL137927; R01 HL089856; and R01 HL147148 (M.H.C.), and K01-HL129039 (D.Q.). Study-specific acknowledgments are given in Supplementary Notes 1–3. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. A full list of authors for the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium is provided at https://www.nhlbiwgs.org/topmed-banner-authorship and in Supplementary Note 4. Funding Information: In the past three years, Edwin K. Silverman and Michael H. Cho have received grant and travel support from GlaxoSmithKline and Bayer. Michael H. Cho has received consulting and speaking fees from Illumina and AstraZeneca. Tuuli Lappalainen is a scientific advisory board member of Variant Bio with equity and Goldfinch Bio. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Goncalo R. Abecasis is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. All other authors have no competing interests to declare.",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-18334-7",

language = "English (US)",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - TOPMed Lung Working Group

AU - Zhao, Xutong

AU - Qiao, Dandi

AU - Yang, Chaojie

AU - Kasela, Silva

AU - Kim, Wonji

AU - Ma, Yanlin

AU - Shrine, Nick

AU - Batini, Chiara

AU - Sofer, Tamar

AU - Taliun, Sarah A.Gagliano

AU - Sakornsakolpat, Phuwanat

AU - Balte, Pallavi P.

AU - Prokopenko, Dmitry

AU - Yu, Bing

AU - Lange, Leslie A.

AU - Dupuis, Josée

AU - Cade, Brian E.

AU - Lee, Jiwon

AU - Gharib, Sina A.

AU - Daya, Michelle

AU - Laurie, Cecelia A.

AU - Ruczinski, Ingo

AU - Cupples, L. Adrienne

AU - Loehr, Laura R.

AU - Bartz, Traci M.

AU - Morrison, Alanna C.

AU - Psaty, Bruce M.

AU - Vasan, Ramachandran S.

AU - Wilson, James G.

AU - Taylor, Kent D.

AU - Durda, Peter

AU - Johnson, W. Craig

AU - Cornell, Elaine

AU - Guo, Xiuqing

AU - Liu, Yongmei

AU - Tracy, Russell P.

AU - Ardlie, Kristin G.

AU - Aguet, François

AU - VanDenBerg, David J.

AU - Papanicolaou, George J.

AU - Rotter, Jerome I.

AU - Barnes, Kathleen C.

AU - Jain, Deepti

AU - Nickerson, Deborah A.

AU - Muzny, Donna M.

AU - Metcalf, Ginger A.

AU - Doddapaneni, Harshavardhan

AU - Dugan-Perez, Shannon

AU - Gupta, Namrata

AU - Kaplan, Robert C.

N1 - Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Atherosclerosis Risk in Communities (ARIC)” (phs001211) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2) and the Broad Institute for MIT and Harvard (3R01HL092577-06S1). WGS for “NHLBI TOPMed: Cardiovascular Health Study (CHS)” (phs001368) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C). WGS for “NHLBI TOPMed: The Cleveland Family Study” (phs000954) was performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Fra-mingham Heart Study” (phs000974) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C and 3R01HL092577-06S1). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1 and HHSN268201500014C). WGS for “NHLBI TOPMed: Boston Early-Onset COPD Study in the TOPMed Program” (phs000946) was performed at the University of Washington Northwest Genomics Center (3R01HL089856-08S1). WGS for “NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene) in the TOPMed Program” (phs000951) was performed at the University of Washington Northwest Genomics Center (3R01 HL089856-08S1) and the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The TOPMed MESA Multi-Omics project was conducted by the University of Washington and LABioMed (HHSN2682015000031/HHSN26800004). Phenotype harmonization for pulmonary traits was contributed by the NHLBI Pooled Cohorts Study with funding from NIH/NHLBI R21 HL121457, R21 HL129924, K23 HL130627, R01 HL077612. This research was supported by a TOPMed Analysis Support Award (through U01 HL117626), NIH/NHLBI R01 HL131565 (A.M.), R01 HL142028 (T.L.), R01 HL135142; R01 HL137927; R01 HL089856; and R01 HL147148 (M.H.C.), and K01-HL129039 (D.Q.). Study-specific acknowledgments are given in Supplementary Notes 1–3. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. A full list of authors for the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium is provided at https://www.nhlbiwgs.org/topmed-banner-authorship and in Supplementary Note 4. Funding Information: In the past three years, Edwin K. Silverman and Michael H. Cho have received grant and travel support from GlaxoSmithKline and Bayer. Michael H. Cho has received consulting and speaking fees from Illumina and AstraZeneca. Tuuli Lappalainen is a scientific advisory board member of Variant Bio with equity and Goldfinch Bio. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Goncalo R. Abecasis is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. All other authors have no competing interests to declare.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

AB - Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

UR - http://www.scopus.com/inward/record.url?scp=85093476366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85093476366&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-18334-7

DO - 10.1038/s41467-020-18334-7

M3 - Article

C2 - 33057025

AN - SCOPUS:85093476366

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5182

ER -