Meta-Analysis

. 2022 Aug;77(8):829-833.

doi: 10.1136/thoraxjnl-2021-218577. Epub 2022 Jun 10.

Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Richard J Allen¹, Amy Stockwell², Justin M Oldham³, Beatriz Guillen-Guio⁴, David A Schwartz^{5

6

7}, Toby M Maher^{8

9

10}, Carlos Flores^{11

12

13}, Imre Noth¹⁴, Brian L Yaspan², R Gisli Jenkins⁸, Louise V Wain^{4

15}; International IPF Genetics Consortium

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK rja34@leicester.ac.uk.
² Genentech Inc, South San Francisco, California, USA.
³ Department of Internal Medicine, University of California Davis, Davis, California, USA.
⁴ Department of Health Sciences, University of Leicester, Leicester, UK.
⁵ Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA.
⁶ Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.
⁷ Department of Immunology, University of Colorado Denver, Denver, Colorado, USA.
⁸ National Heart and Lung Institute, Imperial College, London, UK.
⁹ Royal Brompton and Harefield Hospitals, London, UK.
¹⁰ Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, California, USA.
¹¹ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹² Genomics Division, Instituto Tecnológico y de Energías Renovables SA, Santa Cruz de Tenerife, Spain.
¹³ Research Unit, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.
¹⁴ Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA.
¹⁵ National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.

PMID: 35688625
PMCID: PMC9329250
DOI: 10.1136/thoraxjnl-2021-218577

Meta-Analysis

Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Richard J Allen et al. Thorax. 2022 Aug.

. 2022 Aug;77(8):829-833.

doi: 10.1136/thoraxjnl-2021-218577. Epub 2022 Jun 10.

Authors

Collaborators

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK rja34@leicester.ac.uk.
² Genentech Inc, South San Francisco, California, USA.
³ Department of Internal Medicine, University of California Davis, Davis, California, USA.
⁴ Department of Health Sciences, University of Leicester, Leicester, UK.
⁵ Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA.
⁶ Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.
⁷ Department of Immunology, University of Colorado Denver, Denver, Colorado, USA.
⁸ National Heart and Lung Institute, Imperial College, London, UK.
⁹ Royal Brompton and Harefield Hospitals, London, UK.
¹⁰ Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, California, USA.
¹¹ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹² Genomics Division, Instituto Tecnológico y de Energías Renovables SA, Santa Cruz de Tenerife, Spain.
¹³ Research Unit, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.
¹⁴ Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA.
¹⁵ National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.

PMID: 35688625
PMCID: PMC9329250
DOI: 10.1136/thoraxjnl-2021-218577

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk.

Trial registration: ClinicalTrials.gov NCT01134822 NCT01110694 NCT00957242 NCT00650091 NCT04016181 NCT01071707 NCT02988388 NCT00075998 NCT01872689 NCT00287729 NCT00287716 NCT01366209.

Keywords: Idiopathic pulmonary fibrosis.

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Conflict of interest statement

Competing interests: AS and BLY are employees of Genentech/Roche and hold stock and stock options in Roche. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals unrelated to the submitted work. RGJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte and Vicore. DAS is the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. LW reports research funding from GlaxoSmithKline and Orion Pharma, and consultancy for Galapagos (all outside of the submitted work).

Figures

**Figure 1**
Study design and sample sizes.

**Figure 2**
Manhattan plot. Each point shows a genetic variant with chromosomal position on the x axis and the −log(p value) on the y axis. The grey dashed line shows the genome-wide significance level (p=5×10⁻⁸). Each signal is labelled with the gene implicated by that signal. Genes in grey are the novel loci that do show evidence of replicability. The plot has been truncated at p=10⁻³⁰

See this image and copyright information in PMC

References

1. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018;378(19):1811–23. - PubMed
1. Allen RJ, Guillen-Guio B, Oldham JM, Ma S, Dressen A, Paynton ML, Kraven LM, Obeidat M, Li X, Ng M. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 2020;201(5):564–74. - PMC - PubMed
1. Zhang Y, Zhao M, Guo P, Wang Y, Liu L, Zhao J, Gao L, Yuan Z, Xue F, Zhao J. Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis. EBioMedicine 2021;73:103669. - PMC - PubMed
1. Wang L, Balmat TJ, Antonia AL, Constantine FJ, Henao R, Burke TW, Ingham A, McClain MT, Tsalik EL, Ko ER. An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility. Genome Medicine 2021;13(1):1–19. - PMC - PubMed
1. Duckworth A, Gibbons MA, Allen RJ, Almond H, Beaumont RN, Wood AR, Lunnon K, Lindsay MA, Wain LV, Tyrrell J. Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: A mendelian randomisation study. The Lancet Respiratory Medicine 2021;9(3):285–94. - PubMed

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Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Collaborators

Affiliations

Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Authors

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Affiliations

Abstract

Conflict of interest statement

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