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

Juulia J Partanen; Paavo Häppölä; Wei Zhou; Arto A Lehisto; Mari Ainola; Eva Sutinen; Richard J Allen; Amy D Stockwell; Olivia C Leavy; Justin M Oldham; Beatriz Guillen-Guio; Nancy J Cox; Jibril B Hirbo; David A Schwartz; Tasha E Fingerlin; Carlos Flores; Imre Noth; Brian L Yaspan; R Gisli Jenkins; Louise V Wain; Samuli Ripatti; Matti Pirinen; International IPF Genetics Consortium; Global Biobank Meta-Analysis Initiative (GBMI); Tarja Laitinen; Riitta Kaarteenaho; Marjukka Myllärniemi; Mark J Daly; Jukka T Koskela

doi:10.1016/j.xgen.2022.100181

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

Cell Genom. 2022 Oct 12;2(10):100181. doi: 10.1016/j.xgen.2022.100181.

Authors

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.

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.

Abstract

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