Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Richard J. Allen, Beatriz Guillen-Guio, Justin M. Oldham, Shwu Fan Ma, Amy Dressen, Megan L. Paynton, Luke M. Kraven, Ma'en Obeidat, Xuan Li, Michael Ng, Rebecca Braybrooke, Maria Molina-Molina, Brian D. Hobbs, Rachel K. Putman, Phuwanat Sakornsakolpat, Helen L. Booth, William A. Fahy, Simon P. Hart, Mike R. Hill, Nik HiraniRichard B. Hubbard, Robin J. McAnulty, Ann B. Millar, Vidyia Navaratnam, Eunice Oballa, Helen Parfrey, Gauri Saini, Moira K.B. Whyte, Yingze Zhang, Naftali Kaminski, Ayodeji Adegunsoye, Mary E. Strek, Margaret Neighbors, Xuting R. Sheng, Gunnar Gudmundsson, Vilmundur Gudnason, Hiroto Hatabu, David J. Lederer, Ani Manichaikul, John D. Newell, George T. O'Connor, Victor E. Ortega, Hanfei Xu, Tasha E. Fingerlin, Yohan Bossé, Ke Hao, Philippe Joubert, David C. Nickle, Don D. Sin, Wim Timens, Dominic Furniss, Andrew P. Morris, Krina T. Zondervan, Ian P. Hall, Ian Sayers, Martin D. Tobin, M. Toby, Michael H. Cho, Gary M. Hunninghake, David A. Schwartz, Brian L. Yaspan, Philip L. Molyneaux, Carlos Flores, Imre Noth, R. Gisli Jenkins, Louise V. Wain

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized 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 association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed 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 functional analyses (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. Measurements and Main Results: We identified and replicated threenewgenome-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. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Original languageEnglish (US)
Pages (from-to)564-574
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume201
Issue number5
DOIs
StatePublished - Mar 1 2020

Keywords

  • DEPTOR
  • Epidemiology
  • Genetics
  • KIF15
  • MAD1L1

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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