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

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posted on 2023-05-21, 15:37 authored by Peljto, AL, Blumhagen, RZ, Walts, AD, Cardwell, J, Powers, J, Corte, TJ, Joanne DickinsonJoanne Dickinson, Glaspole, I, Moodley, TP, Koziar Vasakova, M, Bendstrup, E, Davidsen, JR, Borie, R, Crestani, B, Dieude, P, Bonella, F, Costabel, U, Gudmundsson, G, Donnelly, SC, Egan, J, Henry, MT, Keane, MP, Kennedy, MP, McCarthy, C, McElroy, AN, Olaniyi, JA, O'Reilly, KMA, Richeldi, L, Leone, PM, Poletti, V, Puppo, F, Tomassetti, S, Luzzi, V, Kokturk, N, Mogulkoc, N, Fiddler, CA, Hirani, N, Jenkins, G, Maher, TM, Molyneaux, PL, Parfey, PL, Braybrooke, R, Blackwell, TS, Jackson, PD, Nathan, SD, Porteous, MK, Brown, KK, Christie, JD, Collard, HR, Eickelberg, O, Foster, EA, Gibson, KF, Glassberg, M, Kass, D, Kropski, JA, Lederer, D, Linderholm, AL, Loyd, J, Mathai, SK, Montesi, SB, Noth, I, Oldham, JM, Palmisciano, AJ, Reichner, CA, Rojas, M, Roman, J, Schluger, N, Shea, BS, Swigris, JJ, Wolters, PJ, Zhang, Y, Prele, CMA, Enghelmayer, JI, Otaola, M, Ryerson, CJ, Salinas, M, Sterclova, M, Gebremariam, TH, Myllarniemi, M, Carbone, R, Furusawa, H, Hirose, M, Inoue, Y, Miyazaki, Y, Ohta, K, Ohta, S, Okamoto, T, Soon Kim, D, Pardo, A, Selman, M, Aranda, AU, Park, MS, Park, JS, Song, JW, Molina-Molina, M, Planas-Cerezales, L, Westergren-Thorsson, G, Smith, AV, Manichaikul, AW, Kim, JS, Rich, SS, Oelsner, EC, Barr, RG, Rotter, JI, Dupuis, J, O'Connor, G, Vasan, RS, Cho, MH, Silverman, EK, Schwarz, MI, Steele, MP, Lee, JS, Yang, IV, Fingerlin, TE, Schwartz, DA

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.

History

Publication title

American Journal of Respiratory and Critical Care Medicine

ISSN

1073-449X

Department/School

Menzies Institute for Medical Research

Publisher

Amer Thoracic Soc

Place of publication

1740 Broadway, New York, USA, Ny, 10019-4374

Rights statement

Copyright 2023.

Repository Status

  • Restricted

Socio-economic Objectives

Diagnosis of human diseases and conditions; Treatment of human diseases and conditions; Determinants of health

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