Polygenic Risk and Rare Variants in Endotypes of Idiopathic Pulmonary Fibrosis.

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) and telomere length (TL) are both strongly linked to rare and common genetic variation. Shortened TL itself may be causal for IPF. Whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly is unknown.

METHODS

We used whole genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia (777 IPF, 2905 controls) and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls) and the UK Biobank (UKBB, 2739 IPF, 395331 controls). In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalized polygenic risk scores for IPF (IPF-PRS) and telomere length (TL-PRS). Telomere length of blood leukocytes was measured using a qPCR assay for two cohorts. We determined the association of the rs35705950 polymorphism, an IPF-PRS excluding (IPF-PRS-no), and a TL-PRS with IPF risk in the overall cohort and in subgroups stratified by genetic endotypes (rare variant carriers, non-carriers stratified by TL cutoffs). We calculated cross-validated area under the receiver operator curve (AUC) and compared the liability of IPF explained by genetic variables.

FINDINGS

We identified independent associations between IPF risk and rare variants, the SNP, and both polygenic scores in the discovery cohort and replicated these findings in the TOPMed and UKBB cohorts. The adjusted effect size of the TL-PRS, which includes >180 SNPs not previously associated with IPF, was comparable to the IPF-PRS-no in the discovery (OR 1.63 [95% CI 1.47, 1.81] vs. OR 1.60 [1.44, 1.77]) and replication cohorts (TOPMed OR 1.47 [1.36, 1.59] vs. OR 1.37 [1.25, 1.50]; UKBB OR 1.24 [1.19, 1.29] vs. OR 1.25 [1.21, 1.30]). The TL-PRS incrementally improved disease prediction beyond known IPF common and rare genetic predictors and clinical variables in discovery (combined AUC: 0.89, p = 0.006), TOPMed (combined AUC: 0.89, p = 0.01), and UKBB cohorts (combined AUC: 0.77, p = 0.03). Rare and common variants jointly contributed to genetic liability of IPF. The TL-PRS increased liability of IPF explained by 13% in the discovery cohort and 8% and 13% in the TOPMed and UKBB cohorts, respectively. In IPF subjects with damaging rare variants, the TL-PRS was consistently associated with disease risk whereas the IPF-PRS-no was not. The TL-PRS also conferred nominally greater odds of disease risk than the IPF-PRS-no in patients with shorter TL, in the discovery and UKBB cohorts. Together, 23-43% of IPF cases have damaging rare variants or telomeres <10 percentile, where the TL-PRS represents a major unrecognized genetic risk factor.

INTERPRETATION

Common and rare genetic variation confer context-specific genetic risk in IPF competitively and cooperatively. In contrast to known IPF common risk variants, the TL-PRS, which includes >180 genetic loci not previously associated with IPF, increases the risk of disease specifically in certain IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of IPF genetic heterogeneity.

FUNDING

National Institutes of Health (NIH), Medical Research Council (MRC), National Institute for Health and Care Research (NIHR).