Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

Juulia J Partanen¹, Paavo Häppölä¹, Wei Zhou^{2

3

4}, Arto A Lehisto¹, Mari Ainola^{5

6}, Eva Sutinen^{5

6}, Richard J Allen⁷, Amy D Stockwell⁸, Olivia C Leavy⁷, Justin M Oldham⁹, Beatriz Guillen-Guio⁷, Nancy J Cox^{10

11}, Jibril B Hirbo^{10

11}, David A Schwartz¹², Tasha E Fingerlin¹³, Carlos Flores^{14

15

16

17}, Imre Noth¹⁸, Brian L Yaspan⁸, R Gisli Jenkins^{19

20}, Louise V Wain^{7

21}, Samuli Ripatti^{1

22}, Matti Pirinen^{1

23

24}; International IPF Genetics Consortium; Global Biobank Meta-Analysis Initiative (GBMI); Tarja Laitinen²⁵, Riitta Kaarteenaho^{26

27}, Marjukka Myllärniemi^{5

6}, Mark J Daly^{1

2

3

4}, Jukka T Koskela¹

Affiliations

¹ Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Health Sciences, University of Leicester, Leicester, UK.
⁸ Human Genetics, Genentech, South San Francisco, CA, USA.
⁹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA.
¹⁰ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Medicine, University of Colorado, Aurora, CO, USA.
¹³ Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
¹⁴ Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
¹⁵ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹⁶ Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain.
¹⁷ Faculty of Health Sciences, University of Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
¹⁸ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁹ National Heart and Lung Institute, Imperial College London, London, UK.
²⁰ Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²¹ National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²² Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²³ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁴ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
²⁵ Administration Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
²⁶ Research Unit of Internal Medicine, University of Oulu, Oulu, Finland.
²⁷ Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.

PMID: 36777997
PMCID: PMC9903787
DOI: 10.1016/j.xgen.2022.100181

Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

Juulia J Partanen et al. Cell Genom. 2022.

. 2022 Oct 12;2(10):100181.

doi: 10.1016/j.xgen.2022.100181.

Authors

Affiliations

¹ Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Health Sciences, University of Leicester, Leicester, UK.
⁸ Human Genetics, Genentech, South San Francisco, CA, USA.
⁹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA.
¹⁰ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Medicine, University of Colorado, Aurora, CO, USA.
¹³ Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
¹⁴ Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
¹⁵ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
¹⁶ Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain.
¹⁷ Faculty of Health Sciences, University of Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
¹⁸ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁹ National Heart and Lung Institute, Imperial College London, London, UK.
²⁰ Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²¹ National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²² Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²³ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁴ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
²⁵ Administration Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
²⁶ Research Unit of Internal Medicine, University of Oulu, Oulu, Finland.
²⁷ Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.

PMID: 36777997
PMCID: PMC9903787
DOI: 10.1016/j.xgen.2022.100181

Abstract

The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor-the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.

Keywords: COVID-19; GWAS; Global Biobank Meta-Analysis Initiative; MUC5B; ancestry; cross-population analysis; fine-mapping; idiopathic pulmonary fibrosis; meta-analysis.

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Conflict of interest statement

A.S. and B.L.Y. are full-time employees of Genentech with stock and stock options in Roche. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of IPF. T.E.F. is a consultant to Eleven P15. R.G.J. has received research funding from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, RedX, and Pliant; consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, and Pliant; payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi, Roche, PatientMPower, and AstraZeneca; payment for Participation on a Data Safety Monitoring Board or Advisory Board from Boehringer Ingelheim, Galapagos, and Vicore, had a Leadership or fiduciary role in other board, society, committee or advocacy group (unpaid) in NuMedii and Action for Pulmonary Fibrosis; and is a trustee for Action for Pulmonary Fibrosis. L.V.W. has received research funding from GSK and Orion Pharma and consultancy for Galapagos. M.J.D. is a founder of Maze Therapeutics. J.T.K. and M.J.D. are members of the Pfizer Finland FinnGen Advisory Board.

Figures

**Figure 1**
Genome-wide association results for IPF Results from the joint meta-analysis are plotted in the top panel of the Miami plot and results from the GBMI meta-analysis in the bottom panel. Novel associations are highlighted in orange and annotated with the closest gene (index variant and variants in LD at r² > 0.05 are highlighted, except for the *PSKH1* signal for which variants within a 1 Mb window are highlighted due to missing LD information). Variants with p values ≤ 0.01 are plotted.

**Figure 2**
IPF meta-analysis and COVID-19 hospitalization results COVID-19 hospitalization results are shown in the top panel and IPF joint meta-analysis results in the bottom panel. Genome-wide significant IPF signals that reached FDR-adjusted p value < 0.05 in COVID-19 hospitalization scan are highlighted in yellow. Index variants in the IPF scan are plotted as diamonds in the COVID-19 results. Variants with p values ≤ 0.1 are plotted.

**Figure 3**
Effect size estimate comparison latest IPF meta-analysis versus GBMI Scatter plot of absolute value of latest IPF meta-analysis beta against absolute value of meta-analyzed GBMI NFE beta with inverse variance weighted linear regression line (weights from Allen et al. study) and accompanying slope estimate. The analysis was performed within the non-Finnish European ancestry and variants included were genome-wide significant in the joint IPF meta-analysis.

See this image and copyright information in PMC

References

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Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

Affiliations

Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources