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Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants


Peljto, AL and Blumhagen, RZ and Walts, AD and Cardwell, J and Powers, J and Corte, TJ and Dickinson, JL and Glaspole, I and Moodley, TP and Koziar Vasakova, M and Bendstrup, E and Davidsen, JR and Borie, R and Crestani, B and Dieude, P and Bonella, F and Costabel, U and Gudmundsson, G and Donnelly, SC and Egan, J and Henry, MT and Keane, MP and Kennedy, MP and McCarthy, C and McElroy, AN and Olaniyi, JA and O'Reilly, KMA and Richeldi, L and Leone, PM and Poletti, V and Puppo, F and Tomassetti, S and Luzzi, V and Kokturk, N and Mogulkoc, N and Fiddler, CA and Hirani, N and Jenkins, G and Maher, TM and Molyneaux, PL and Parfey, PL and Braybrooke, R and Blackwell, TS and Jackson, PD and Nathan, SD and Porteous, MK and Brown, KK and Christie, JD and Collard, HR and Eickelberg, O and Foster, EA and Gibson, KF and Glassberg, M and Kass, D and Kropski, JA and Lederer, D and Linderholm, AL and Loyd, J and Mathai, SK and Montesi, SB and Noth, I and Oldham, JM and Palmisciano, AJ and Reichner, CA and Rojas, M and Roman, J and Schluger, N and Shea, BS and Swigris, JJ and Wolters, PJ and Zhang, Y and Prele, CMA and Enghelmayer, JI and Otaola, M and Ryerson, CJ and Salinas, M and Sterclova, M and Gebremariam, TH and Myllarniemi, M and Carbone, R and Furusawa, H and Hirose, M and Inoue, Y and Miyazaki, Y and Ohta, K and Ohta, S and Okamoto, T and Soon Kim, D and Pardo, A and Selman, M and Aranda, AU and Park, MS and Park, JS and Song, JW and Molina-Molina, M and Planas-Cerezales, L and Westergren-Thorsson, G and Smith, AV and Manichaikul, AW and Kim, JS and Rich, SS and Oelsner, EC and Barr, RG and Rotter, JI and Dupuis, J and O'Connor, G and Vasan, RS and Cho, MH and Silverman, EK and Schwarz, MI and Steele, MP and Lee, JS and Yang, IV and Fingerlin, TE and Schwartz, DA, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants, American Journal of Respiratory and Critical Care Medicine ISSN 1073-449X (2023) [Refereed Article]

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DOI: doi:10.1164/rccm.202207-1331OC


Rationale: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown.

Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk.

Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants.

Measurements and main results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%).

Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Item Details

Item Type:Refereed Article
Keywords:pulmonary fibrosis, genetic predisposition
Research Division:Biomedical and Clinical Sciences
Research Group:Cardiovascular medicine and haematology
Research Field:Respiratory diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Dickinson, JL (Professor Joanne Dickinson)
ID Code:154783
Year Published:2023
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-01-06
Last Modified:2023-01-12

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