Genetic Associations and Architecture of Asthma-COPD Overlap

Catherine John; Anna L Guyatt; Nick Shrine; Richard Packer; Thorunn A Olafsdottir; Jiangyuan Liu; Lystra P Hayden; Su H Chu; Jukka T Koskela; Jian'an Luan; Xingnan Li; Natalie Terzikhan; Hanfei Xu; Traci M Bartz; Hans Petersen; Shuguang Leng; Steven A Belinsky; Aivaras Cepelis; Ana I Hernández Cordero; Ma'en Obeidat; Gudmar Thorleifsson; Deborah A Meyers; Eugene R Bleecker; Lori C Sakoda; Carlos Iribarren; Yohannes Tesfaigzi; Sina A Gharib; Josée Dupuis; Guy Brusselle; Lies Lahousse; Victor E Ortega; Ingileif Jonsdottir; Don D Sin; Yohan Bossé; Maarten van den Berge; David Nickle; Jennifer K Quint; Ian Sayers; Ian P Hall; Claudia Langenberg; Samuli Ripatti; Tarja Laitinen; Ann C Wu; Jessica Lasky-Su; Per Bakke; Amund Gulsvik; Craig P Hersh; Caroline Hayward; Arnulf Langhammer; Ben Brumpton; Kari Stefansson; Michael H Cho; Louise V Wain; Martin D Tobin

doi:10.1016/j.chest.2021.12.674

Genetic Associations and Architecture of Asthma-COPD Overlap

Catherine John, Anna L Guyatt, Nick Shrine, Richard Packer, Thorunn A Olafsdottir, Jiangyuan Liu, Lystra P Hayden, Su H Chu, Jukka T Koskela, Jian'an Luan, Xingnan Li, Natalie Terzikhan, Hanfei Xu, Traci M Bartz, Hans Petersen, Shuguang Leng, Steven A Belinsky, Aivaras Cepelis, Ana I Hernández Cordero, Ma'en ObeidatGudmar Thorleifsson, Deborah A Meyers, Eugene R Bleecker, Lori C Sakoda, Carlos Iribarren, Yohannes Tesfaigzi, Sina A Gharib, Josée Dupuis, Guy Brusselle, Lies Lahousse, Victor E Ortega, Ingileif Jonsdottir, Don D Sin, Yohan Bossé, Maarten van den Berge, David Nickle, Jennifer K Quint, Ian Sayers, Ian P Hall, Claudia Langenberg, Samuli Ripatti, Tarja Laitinen, Ann C Wu, Jessica Lasky-Su, Per Bakke, Amund Gulsvik, Craig P Hersh, Caroline Hayward, Arnulf Langhammer, Ben Brumpton, Kari Stefansson, Michael H Cho, Louise V Wain, Martin D Tobin

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

Abstract / Description of output

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.

RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?

STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).

RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.

INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Original language	English
Pages (from-to)	1155-1166
Number of pages	12
Journal	Chest Journal
Volume	161
Issue number	5
Early online date	31 Jan 2022
DOIs	https://doi.org/10.1016/j.chest.2021.12.674
Publication status	E-pub ahead of print - 31 Jan 2022

Keywords / Materials (for Non-textual outputs)

Asthma/diagnosis
Genome-Wide Association Study
Humans
Lung
Pulmonary Disease, Chronic Obstructive/complications
Smoking/genetics

Access to Document

10.1016/j.chest.2021.12.674Licence: Creative Commons: Attribution (CC-BY)

OA_PIIS0012369222001982Final published version, 658 KBLicence: CC BY

Cite this

John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., ... Tobin, M. D. (2022). Genetic Associations and Architecture of Asthma-COPD Overlap. Chest Journal, 161(5), 1155-1166. Advance online publication. https://doi.org/10.1016/j.chest.2021.12.674

@article{34116ffb22c74d72914ca861a510aeb1,

title = "Genetic Associations and Architecture of Asthma-COPD Overlap",

abstract = "BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.",

keywords = "Asthma/diagnosis, Genome-Wide Association Study, Humans, Lung, Pulmonary Disease, Chronic Obstructive/complications, Smoking/genetics",

author = "Catherine John and Guyatt, {Anna L} and Nick Shrine and Richard Packer and Olafsdottir, {Thorunn A} and Jiangyuan Liu and Hayden, {Lystra P} and Chu, {Su H} and Koskela, {Jukka T} and Jian'an Luan and Xingnan Li and Natalie Terzikhan and Hanfei Xu and Bartz, {Traci M} and Hans Petersen and Shuguang Leng and Belinsky, {Steven A} and Aivaras Cepelis and {Hern{\'a}ndez Cordero}, {Ana I} and Ma'en Obeidat and Gudmar Thorleifsson and Meyers, {Deborah A} and Bleecker, {Eugene R} and Sakoda, {Lori C} and Carlos Iribarren and Yohannes Tesfaigzi and Gharib, {Sina A} and Jos{\'e}e Dupuis and Guy Brusselle and Lies Lahousse and Ortega, {Victor E} and Ingileif Jonsdottir and Sin, {Don D} and Yohan Boss{\'e} and {van den Berge}, Maarten and David Nickle and Quint, {Jennifer K} and Ian Sayers and Hall, {Ian P} and Claudia Langenberg and Samuli Ripatti and Tarja Laitinen and Wu, {Ann C} and Jessica Lasky-Su and Per Bakke and Amund Gulsvik and Hersh, {Craig P} and Caroline Hayward and Arnulf Langhammer and Ben Brumpton and Kari Stefansson and Cho, {Michael H} and Wain, {Louise V} and Tobin, {Martin D}",

year = "2022",

month = jan,

day = "31",

doi = "10.1016/j.chest.2021.12.674",

language = "English",

volume = "161",

pages = "1155--1166",

journal = "Chest Journal",

issn = "0012-3692",

publisher = "American College of Chest Physicians (ACCP) ",

number = "5",

}

John, C, Guyatt, AL, Shrine, N, Packer, R, Olafsdottir, TA, Liu, J, Hayden, LP, Chu, SH, Koskela, JT, Luan, J, Li, X, Terzikhan, N, Xu, H, Bartz, TM, Petersen, H, Leng, S, Belinsky, SA, Cepelis, A, Hernández Cordero, AI, Obeidat, M, Thorleifsson, G, Meyers, DA, Bleecker, ER, Sakoda, LC, Iribarren, C, Tesfaigzi, Y, Gharib, SA, Dupuis, J, Brusselle, G, Lahousse, L, Ortega, VE, Jonsdottir, I, Sin, DD, Bossé, Y, van den Berge, M, Nickle, D, Quint, JK, Sayers, I, Hall, IP, Langenberg, C, Ripatti, S, Laitinen, T, Wu, AC, Lasky-Su, J, Bakke, P, Gulsvik, A, Hersh, CP, Hayward, C, Langhammer, A, Brumpton, B, Stefansson, K, Cho, MH, Wain, LV & Tobin, MD 2022, 'Genetic Associations and Architecture of Asthma-COPD Overlap', Chest Journal, vol. 161, no. 5, pp. 1155-1166. https://doi.org/10.1016/j.chest.2021.12.674

TY - JOUR

T1 - Genetic Associations and Architecture of Asthma-COPD Overlap

AU - John, Catherine

AU - Guyatt, Anna L

AU - Shrine, Nick

AU - Packer, Richard

AU - Olafsdottir, Thorunn A

AU - Liu, Jiangyuan

AU - Hayden, Lystra P

AU - Chu, Su H

AU - Koskela, Jukka T

AU - Luan, Jian'an

AU - Li, Xingnan

AU - Terzikhan, Natalie

AU - Xu, Hanfei

AU - Bartz, Traci M

AU - Petersen, Hans

AU - Leng, Shuguang

AU - Belinsky, Steven A

AU - Cepelis, Aivaras

AU - Hernández Cordero, Ana I

AU - Obeidat, Ma'en

AU - Thorleifsson, Gudmar

AU - Meyers, Deborah A

AU - Bleecker, Eugene R

AU - Sakoda, Lori C

AU - Iribarren, Carlos

AU - Tesfaigzi, Yohannes

AU - Gharib, Sina A

AU - Dupuis, Josée

AU - Brusselle, Guy

AU - Lahousse, Lies

AU - Ortega, Victor E

AU - Jonsdottir, Ingileif

AU - Sin, Don D

AU - Bossé, Yohan

AU - van den Berge, Maarten

AU - Nickle, David

AU - Quint, Jennifer K

AU - Sayers, Ian

AU - Hall, Ian P

AU - Langenberg, Claudia

AU - Ripatti, Samuli

AU - Laitinen, Tarja

AU - Wu, Ann C

AU - Lasky-Su, Jessica

AU - Bakke, Per

AU - Gulsvik, Amund

AU - Hersh, Craig P

AU - Hayward, Caroline

AU - Langhammer, Arnulf

AU - Brumpton, Ben

AU - Stefansson, Kari

AU - Cho, Michael H

AU - Wain, Louise V

AU - Tobin, Martin D

PY - 2022/1/31

Y1 - 2022/1/31

N2 - BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

AB - BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

KW - Asthma/diagnosis

KW - Genome-Wide Association Study

KW - Humans

KW - Lung

KW - Pulmonary Disease, Chronic Obstructive/complications

KW - Smoking/genetics

U2 - 10.1016/j.chest.2021.12.674

DO - 10.1016/j.chest.2021.12.674

M3 - Article

C2 - 35104449

SN - 0012-3692

VL - 161

SP - 1155

EP - 1166

JO - Chest Journal

JF - Chest Journal

IS - 5

ER -

Genetic Associations and Architecture of Asthma-COPD Overlap

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Cite this