Genetic variants underpinning lung function decline in the Lifelines general population cohort study

Rationale Variations in age-related lung function decline are associated with genetic and environmental factors. The genetic variants contributing to this decline remain largely unknown, limiting the understanding of individual susceptibility and potential interventions. Objectives This study aims to uncover the genetic factors associated with lung function decline, using the Lifelines cohort study. Methods Longitudinal data covering 3 visits over approximately 15 years were available. Genotyping and longitudinal spirometry data were present for 24 749 subjects aged 25 or older at baseline. A three-step approach was used. First, lung function change over time was estimated using a linear-mixed effect model. Second, a genome-wide association study for the estimated change was conducted, adjusting for age, sex, smoking load and the first 10 principal components. Third, single nucleotide polymorphisms (SNPs) with p-value <1×10 −5 were analysed using a linear-mixed effect model. Selected SNPs were tested in two independent cohorts (N=1376 and N=27 249), followed by meta-analysis. Measurements and Main Results Among the included individuals, 19 722 had spirometry at two timepoints and 5027 at three, with median IQR follow-up of 8.1 4.4, 10.4 and 12.1 11, 13.6 years, respectively. We identified 67 variants suggestively associated with lung function decline (p<1×10 −5 ). Rs150094594, was significant (p=0.007) in a replication cohort with consistent effect direction. This intergenic variant, not previously reported, reached genome-wide significance in the meta-analysis (rs150094594:T, β( se ): 15.9(2.7) ml/year, p-value=3.9×10 −9 ). Conclusions This study shows a role of genetics in lung function decline, emphasizing the importance of exploring the interplay between genetic and environmental factors.