2381/11347544.v1 Richard Allen Richard Allen Beatriz Guillen-Guio Beatriz Guillen-Guio Justin M Oldham Justin M Oldham Shwu-Fan Ma Shwu-Fan Ma Amy Dressen Amy Dressen megan paynton megan paynton luke kraven luke kraven Ma'en Obeida Ma'en Obeida Xuan Li Xuan Li Michael Ng Michael Ng Rebecca Braybrooke Rebecca Braybrooke Maria Molina-Molina Maria Molina-Molina Brian D Hobbs Brian D Hobbs Rachel K Putman Rachel K Putman Phuwanat Sakornsakolpat Phuwanat Sakornsakolpat Helen L Booth Helen L Booth William A Fahy William A Fahy Simon P Hart Simon P Hart Mike R Hill Mike R Hill Nik Hirani Nik Hirani Richard B Hubbard Richard B Hubbard Robin J McAnulty Robin J McAnulty Ann B Millar Ann B Millar Vidyia Navaratnam Vidyia Navaratnam Eunice Oballa Eunice Oballa Helen Parfrey Helen Parfrey Gauri Saini Gauri Saini Yingze Zhang Yingze Zhang Naftali Kaminski Naftali Kaminski Ayodeji Adegunsoye Ayodeji Adegunsoye Mary E Strek Mary E Strek Margaret Neighbors Margaret Neighbors Xuting R Sheng Xuting R Sheng Gunnar Gudmundsson Gunnar Gudmundsson Vilmundur Gudnason Vilmundur Gudnason Hiroto Hatabu Hiroto Hatabu David J Lederer David J Lederer Ani Manichaikul Ani Manichaikul John D Newell Jr John D Newell Jr George T O'Connor George T O'Connor Victor E Ortega Victor E Ortega Hanfei Xu Hanfei Xu Tasha E Fingerlin Tasha E Fingerlin Yohan Bossé Yohan Bossé Ke Hao Ke Hao Philippe Joubert Philippe Joubert David C Nickle David C Nickle Don D Sin Don D Sin Wim Timens Wim Timens Dominic Furniss Dominic Furniss Andrew P Morris Andrew P Morris Krina Zondervan Krina Zondervan Ian P Hall Ian P Hall Ian Sayers Ian Sayers Martin D Tobin Martin D Tobin Toby M Maher Toby M Maher Michael H Cho Michael H Cho Gary M Hunninghake Gary M Hunninghake David A Schwartz David A Schwartz Brian L Yaspan Brian L Yaspan Philip L Molyneaux Philip L Molyneaux Carlos Flores Carlos Flores Imre Noth Imre Noth R Gisli Jenkins R Gisli Jenkins Louise V Wain Louise V Wain Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis University of Leicester 2020 Idiopathic Pulmonary Fibrosis Genetics epidemiology KIF15 MAD1L1 DEPTOR 2020-04-29 14:38:15 Journal contribution https://figshare.le.ac.uk/articles/journal_contribution/Genome-Wide_Association_Study_of_Susceptibility_to_Idiopathic_Pulmonary_Fibrosis/11347544 Rationale: Idiopathic 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. Genome-wide association studies have reported signals of associationimplicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.<div>Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.<br></div><div>Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functionalanalyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.<br></div><div>Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility.<br></div><div>Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.<br></div>