Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Allen, R. J.; Guillen-Guio, B.; Oldham, J. M.; Ma, S.-F.; Dressen, A.; Paynton, M. L.; Kraven, L. M.; Obeidat, M.; Li, X.; Ng, M.; Braybrooke, R.; Molina-Molina, M.; Hobbs, B. D.; Putman, R. K.; Sakornsakolpat, P.; Booth, H. L.; Fahy, W. A.; Hart, S. P.; Hill, M. R.; Hirani, N.; Hubbard, R. B.; McAnulty, R. J.; Millar, A. B.; Navaratnam, V.; Oballa, E.; Parfrey, H.; Saini, G.; Whyte, M. K.; Gudmundsson, G.; Gudnason, V.; Hatabu, H.; Lederer, D. J.; Manichaikul, A.; Newell, J. D.; O'Connor, G. T.; Ortega, V. E.; Xu, H.; Fingerlin, T. E.; Bosse, Y.; Hao, K.; Joubert, P.; Nickle, D. C.; Sin, D.

doi:10.1101/636761

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bioRxiv · 10.1101/636761

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

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Abstract

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.\n\nObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.\n\nMethods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.\n\nMain resultsWe identified and replicated three new genome-wide significant (P<5x10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.\n\nConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

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Allen, R. J., Guillen-Guio, B., Oldham, J. M., Ma, S.-F., Dressen, A., Paynton, M. L., Kraven, L. M., Obeidat, M., Li, X., Ng, M., Braybrooke, R., Molina-Molina, M., Hobbs, B. D., Putman, R. K., Sakornsakolpat, P., Booth, H. L., Fahy, W. A., Hart, S. P., Hill, M. R., Hirani, N., Hubbard, R. B., McAnulty, R. J., Millar, A. B., Navaratnam, V., Oballa, E., Parfrey, H., Saini, G., Whyte, M. K., Gudmundsson, G., Gudnason, V., Hatabu, H., Lederer, D. J., Manichaikul, A., Newell, J. D., O'Connor, G. T., Ortega, V. E., Xu, H., Fingerlin, T. E., Bosse, Y., Hao, K., Joubert, P., Nickle, D. C., Sin, D.. 2019-05-14. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. https://doi.org/10.1101/636761

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