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@article{Allen:2020:10.1164/rccm.201905-1017oc,
author = {Allen, RJ and Guillen-Guio, B and Oldham, JM and Ma, S-F and Dressen, A and Paynton, ML and Kraven, LM and Obeidat, M and Li, X and Ng, M and Braybrooke, R and Molina-Molina, M and Hobbs, BD and Putman, RK and Sakornsakolpat, P and Booth, HL and Fahy, WA and Hart, SP and Hill, MR and Hirani, N and Hubbard, RB and McAnulty, RJ and Millar, AB and Navaratnam, V and Oballa, E and Parfrey, H and Saini, G and Whyte, MKB and Zhang, Y and Kaminski, N and Adegunsoye, A and Strek, ME and Neighbors, M and Sheng, XR and Gudmundsson, G and Gudnason, V and Hatabu, H and Lederer, DJ and Manichaikul, A and Newell, Jr JD and O'Connor, GT and Ortega, VE and Xu, H and Fingerlin, TE and Bossé, Y and Hao, K and Joubert, P and Nickle, DC and Sin, DD and Timens, W and Furniss, D and Morris, AP and Zondervan, K and Hall, IP and Sayers, I and Tobin, MD and Maher, TM and Cho, MH and Hunninghake, GM and Schwartz, DA and Yaspan, BL and Molyneaux, PL and Flores, C and Noth, I and Jenkins, RG and Wain, LV},
doi = {10.1164/rccm.201905-1017oc},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {564--574},
title = {Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis},
url = {http://dx.doi.org/10.1164/rccm.201905-1017oc},
volume = {201},
year = {2020}
}

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TY  - JOUR
AB  - 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 association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. 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 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. 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. 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.
AU  - Allen,RJ
AU  - Guillen-Guio,B
AU  - Oldham,JM
AU  - Ma,S-F
AU  - Dressen,A
AU  - Paynton,ML
AU  - Kraven,LM
AU  - Obeidat,M
AU  - Li,X
AU  - Ng,M
AU  - Braybrooke,R
AU  - Molina-Molina,M
AU  - Hobbs,BD
AU  - Putman,RK
AU  - Sakornsakolpat,P
AU  - Booth,HL
AU  - Fahy,WA
AU  - Hart,SP
AU  - Hill,MR
AU  - Hirani,N
AU  - Hubbard,RB
AU  - McAnulty,RJ
AU  - Millar,AB
AU  - Navaratnam,V
AU  - Oballa,E
AU  - Parfrey,H
AU  - Saini,G
AU  - Whyte,MKB
AU  - Zhang,Y
AU  - Kaminski,N
AU  - Adegunsoye,A
AU  - Strek,ME
AU  - Neighbors,M
AU  - Sheng,XR
AU  - Gudmundsson,G
AU  - Gudnason,V
AU  - Hatabu,H
AU  - Lederer,DJ
AU  - Manichaikul,A
AU  - Newell,Jr JD
AU  - O'Connor,GT
AU  - Ortega,VE
AU  - Xu,H
AU  - Fingerlin,TE
AU  - Bossé,Y
AU  - Hao,K
AU  - Joubert,P
AU  - Nickle,DC
AU  - Sin,DD
AU  - Timens,W
AU  - Furniss,D
AU  - Morris,AP
AU  - Zondervan,K
AU  - Hall,IP
AU  - Sayers,I
AU  - Tobin,MD
AU  - Maher,TM
AU  - Cho,MH
AU  - Hunninghake,GM
AU  - Schwartz,DA
AU  - Yaspan,BL
AU  - Molyneaux,PL
AU  - Flores,C
AU  - Noth,I
AU  - Jenkins,RG
AU  - Wain,LV
DO  - 10.1164/rccm.201905-1017oc
EP  - 574
PY  - 2020///
SN  - 1073-449X
SP  - 564
TI  - Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.201905-1017oc
UR  - https://www.atsjournals.org/doi/10.1164/rccm.201905-1017OC
UR  - http://hdl.handle.net/10044/1/74693
VL  - 201
ER  -

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