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>