The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
Background: few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

Methods: in this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.

Findings: we included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).

Interpretation: we found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.
2213-2600
20-34
Shrine, Nick
1260ae0e-f0fa-4270-9ab0-7b673fdd1c9f
Portelli, Michael A
704a16d0-d1e3-46a8-986c-cb6ef81a53f9
John, Catherine
b90fe53f-facb-432c-b463-0ee29f371b01
Soler Artigas, María
289559fc-f5df-46c0-bf5e-1536f6d0f083
Bennett, Neil
127c40d5-c17e-40b4-856e-de81a5f8e449
Hall, Robert
246e47f0-a0d1-430e-9cef-2b00b3bc046c
Lewis, Jon
d5459c31-9638-4381-a6cf-beb3ce0faf99
Henry, Amanda P
559d5750-a9f2-4909-875d-33d36f577d63
Billington, Charlotte K
5ad46d56-b892-411e-a849-88ec59d3e58b
Ahmad, Azaz
94ebf8ac-1286-4630-be5a-9bfd2f5c5f42
Packer, Richard J
8181eab3-7af5-4488-919c-d25040d0cad9
Shaw, Dominick
ccd4b59e-6012-466f-9de4-8b4dde635328
Pogson, Zara E K
ff546d19-22b7-43bd-ac22-700b2dd26976
Fogarty, Andrew
a02701a9-ab8f-4bc5-a4fa-1aedd81e5065
Mckeever, Tricia M
02c2a3e4-2bc7-4b61-9f45-f3280891693d
Singapuri, Amisha
329da062-1999-4021-bf7f-e361bb2a49a4
Heaney, Liam G
80e8956f-63cb-4637-b916-9b13f3420761
Mansur, Adel H
041b5d7b-7822-4d58-a471-bacb21673fef
Chaudhuri, Rekha
25061dc1-b61f-40d5-a6b0-40840d701aea
Thomson, Neil C
85a6145d-cb2b-4c46-9667-1fd9e4ea977d
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Lockett, Gabrielle A
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Howarth, Peter H
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Hankinson, Jenny
d6b90901-1910-48b7-a54d-f7789e93e85b
Niven, Robert
0355e40e-e0e4-4e85-b4aa-7d2ac529f6df
Simpson, Angela
5591f945-0ead-46a3-a866-b7bea84a2a83
Chung, Kian Fan
33cf2f88-c721-4573-8d6d-ea8da6b0498f
Sterk, Peter J
cffc8681-7dc8-4328-ac93-4d5d5c4319b9
Blakey, John D
56ba3673-4fb8-43ca-989f-5d13ed0c09b5
Adcock, Ian M
e803eb97-a3dc-4de6-a090-9f41498cca1e
Hu, Sile
d5c34deb-1650-44bb-a70f-50c35a6e6ce7
Guo, Yike
d6d31305-f913-4954-ba68-5c0ee7fc17be
Obeidat, Maen
7ca22604-85e3-41ee-94a5-22aea747682f
Sin, Don D
5587bd44-fa37-49be-a4b6-fb08fb38f2f6
Van Den Berge, Maarten
998f7d7f-9878-4bf9-8734-dcfe65aff04e
Nickle, David C
fcc5f6e6-30ce-436e-b5af-76db8dedce2a
Bossé, Yohan
787cbcb1-924c-44a2-9c7a-7f05926238fc
Tobin, Martin D
b732834c-d937-4f6a-a2eb-2669c118b167
Hall, Ian P
a58b8b48-5b81-41e1-9172-d490b1fe58a4
Brightling, Christopher E
b3f869e5-2e62-4a1f-868c-2de15875f55e
Wain, Louise V
3fa0e39c-3251-4095-b99d-5bc224dbb7ae
Sayers, Ian
8595fc2e-102b-406c-ba26-269b8bdba786
Shrine, Nick
1260ae0e-f0fa-4270-9ab0-7b673fdd1c9f
Portelli, Michael A
704a16d0-d1e3-46a8-986c-cb6ef81a53f9
John, Catherine
b90fe53f-facb-432c-b463-0ee29f371b01
Soler Artigas, María
289559fc-f5df-46c0-bf5e-1536f6d0f083
Bennett, Neil
127c40d5-c17e-40b4-856e-de81a5f8e449
Hall, Robert
246e47f0-a0d1-430e-9cef-2b00b3bc046c
Lewis, Jon
d5459c31-9638-4381-a6cf-beb3ce0faf99
Henry, Amanda P
559d5750-a9f2-4909-875d-33d36f577d63
Billington, Charlotte K
5ad46d56-b892-411e-a849-88ec59d3e58b
Ahmad, Azaz
94ebf8ac-1286-4630-be5a-9bfd2f5c5f42
Packer, Richard J
8181eab3-7af5-4488-919c-d25040d0cad9
Shaw, Dominick
ccd4b59e-6012-466f-9de4-8b4dde635328
Pogson, Zara E K
ff546d19-22b7-43bd-ac22-700b2dd26976
Fogarty, Andrew
a02701a9-ab8f-4bc5-a4fa-1aedd81e5065
Mckeever, Tricia M
02c2a3e4-2bc7-4b61-9f45-f3280891693d
Singapuri, Amisha
329da062-1999-4021-bf7f-e361bb2a49a4
Heaney, Liam G
80e8956f-63cb-4637-b916-9b13f3420761
Mansur, Adel H
041b5d7b-7822-4d58-a471-bacb21673fef
Chaudhuri, Rekha
25061dc1-b61f-40d5-a6b0-40840d701aea
Thomson, Neil C
85a6145d-cb2b-4c46-9667-1fd9e4ea977d
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Lockett, Gabrielle A
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Howarth, Peter H
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Hankinson, Jenny
d6b90901-1910-48b7-a54d-f7789e93e85b
Niven, Robert
0355e40e-e0e4-4e85-b4aa-7d2ac529f6df
Simpson, Angela
5591f945-0ead-46a3-a866-b7bea84a2a83
Chung, Kian Fan
33cf2f88-c721-4573-8d6d-ea8da6b0498f
Sterk, Peter J
cffc8681-7dc8-4328-ac93-4d5d5c4319b9
Blakey, John D
56ba3673-4fb8-43ca-989f-5d13ed0c09b5
Adcock, Ian M
e803eb97-a3dc-4de6-a090-9f41498cca1e
Hu, Sile
d5c34deb-1650-44bb-a70f-50c35a6e6ce7
Guo, Yike
d6d31305-f913-4954-ba68-5c0ee7fc17be
Obeidat, Maen
7ca22604-85e3-41ee-94a5-22aea747682f
Sin, Don D
5587bd44-fa37-49be-a4b6-fb08fb38f2f6
Van Den Berge, Maarten
998f7d7f-9878-4bf9-8734-dcfe65aff04e
Nickle, David C
fcc5f6e6-30ce-436e-b5af-76db8dedce2a
Bossé, Yohan
787cbcb1-924c-44a2-9c7a-7f05926238fc
Tobin, Martin D
b732834c-d937-4f6a-a2eb-2669c118b167
Hall, Ian P
a58b8b48-5b81-41e1-9172-d490b1fe58a4
Brightling, Christopher E
b3f869e5-2e62-4a1f-868c-2de15875f55e
Wain, Louise V
3fa0e39c-3251-4095-b99d-5bc224dbb7ae
Sayers, Ian
8595fc2e-102b-406c-ba26-269b8bdba786

Shrine, Nick, Portelli, Michael A, John, Catherine, Soler Artigas, María, Bennett, Neil, Hall, Robert, Lewis, Jon, Henry, Amanda P, Billington, Charlotte K, Ahmad, Azaz, Packer, Richard J, Shaw, Dominick, Pogson, Zara E K, Fogarty, Andrew, Mckeever, Tricia M, Singapuri, Amisha, Heaney, Liam G, Mansur, Adel H, Chaudhuri, Rekha, Thomson, Neil C, Holloway, John W, Lockett, Gabrielle A, Howarth, Peter H, Djukanovic, Ratko, Hankinson, Jenny, Niven, Robert, Simpson, Angela, Chung, Kian Fan, Sterk, Peter J, Blakey, John D, Adcock, Ian M, Hu, Sile, Guo, Yike, Obeidat, Maen, Sin, Don D, Van Den Berge, Maarten, Nickle, David C, Bossé, Yohan, Tobin, Martin D, Hall, Ian P, Brightling, Christopher E, Wain, Louise V and Sayers, Ian (2019) Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study. The Lancet Respiratory Medicine, 7 (1), 20-34. (doi:10.1016/S2213-2600(18)30389-8).

Record type: Article

Abstract

Background: few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

Methods: in this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.

Findings: we included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).

Interpretation: we found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.

Text
IS120918_Main_THELANCETRM-D-18-00478R1_unmarked - Accepted Manuscript
Download (364kB)
Text
Moderate-to-severe asthma - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)
Text
Table 2_NEW_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Table 1 _NEW_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Online_Suppl_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Figure 5_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Figure 4_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Figure 1_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Figure 2_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy
Text
Figure 3_THELANCETRM-D-18-00478 - Other
Restricted to Repository staff only
Request a copy

Show all 10 downloads.

More information

Accepted/In Press date: 14 September 2018
e-pub ahead of print date: 11 December 2018
Published date: 1 January 2019

Identifiers

Local EPrints ID: 426963
URI: http://eprints.soton.ac.uk/id/eprint/426963
ISSN: 2213-2600
PURE UUID: 447dade3-0260-4d7c-8fb7-e4859e461144
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

Catalogue record

Date deposited: 19 Dec 2018 17:30
Last modified: 26 Nov 2021 05:51

Export record

Altmetrics

Contributors

Author: Nick Shrine
Author: Michael A Portelli
Author: Catherine John
Author: María Soler Artigas
Author: Neil Bennett
Author: Robert Hall
Author: Jon Lewis
Author: Amanda P Henry
Author: Charlotte K Billington
Author: Azaz Ahmad
Author: Richard J Packer
Author: Dominick Shaw
Author: Zara E K Pogson
Author: Andrew Fogarty
Author: Tricia M Mckeever
Author: Amisha Singapuri
Author: Liam G Heaney
Author: Adel H Mansur
Author: Rekha Chaudhuri
Author: Neil C Thomson
Author: John W Holloway ORCID iD
Author: Gabrielle A Lockett
Author: Peter H Howarth
Author: Jenny Hankinson
Author: Robert Niven
Author: Angela Simpson
Author: Kian Fan Chung
Author: Peter J Sterk
Author: John D Blakey
Author: Ian M Adcock
Author: Sile Hu
Author: Yike Guo
Author: Maen Obeidat
Author: Don D Sin
Author: Maarten Van Den Berge
Author: David C Nickle
Author: Yohan Bossé
Author: Martin D Tobin
Author: Ian P Hall
Author: Christopher E Brightling
Author: Louise V Wain
Author: Ian Sayers

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×