Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk.

Trial registration: ClinicalTrials.gov NCT01134822 NCT01110694 NCT00957242 NCT00650091 NCT04016181 NCT01071707 NCT02988388 NCT00075998 NCT01872689 NCT00287729 NCT00287716 NCT01366209.

Keywords: Idiopathic pulmonary fibrosis.

Conflict of interest statement

Competing interests: AS and BLY are employees of Genentech/Roche and hold stock and stock options in Roche. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals unrelated to the submitted work. RGJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte and Vicore. DAS is the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. LW reports research funding from GlaxoSmithKline and Orion Pharma, and consultancy for Galapagos (all outside of the submitted work).

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design and sample sizes.

Figure 2

Manhattan plot. Each point shows a genetic variant with chromosomal position on the x axis and the −log(p value) on the y axis. The grey dashed line shows the genome-wide significance level (p=5×10−8). Each signal is labelled with the gene implicated by that signal. Genes in grey are the novel loci that do show evidence of replicability. The plot has been truncated at p=10−30