A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities

Abstract

<b>Rationale:</b> In addition to rare genetic variants and the <i>MUC5B</i> locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the <i>MUC5B</i> locus for IPF and interstitial lung abnormalities (ILAs) is unknown. <b>Objectives:</b> We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the <i>MUC5B</i> region on IPF, ILA, and ILA progression. <b>Methods:</b> We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the <i>MUC5B</i> region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. <b>Measurements and Main Results:</b> We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; <i>P</i> = 7.1 × 10^-95) and PRS-NO-M5B (OR per SD, 2.8; <i>P</i> = 2.5 × 10^-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. <b>Conclusions:</b> A common genetic variant risk score complements the <i>MUC5B</i> variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.