Genetic variants underpinning lung function decline in the Lifelines cohort study

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Genetic and environmental factors are both key contributors to age-related variantions in lung function decline. However, the genetic factors remain largely unidentified, hindering the understanding of individual susceptibility and potential interventions. We aimed to unravel the genetic variants associated with lung function decline in the population-based Lifelines cohort study. Participants over 25 years and with at least 2 valid spirometries were included (n=24749). A genome-wide association study (GWAS) for lung function decline (mL/year) was conducted, adjusted for sex, age, smoking, and the first 10 principal components. Relevant SNPs were selected for replication in Vlagtwedde-Vlaardingen (N=1376) and CHARGE-SpiroMeta (N=27249) cohorts, using a linear mixed effects model. The three cohorts were meta-analysed. Participants from Lifelines had a mean age of 45±11 years, 60% women and mainly never (45%) or ex-smokers (36%). Participants had a mean FEV1 at baseline of 3.48L and a mean FEV1 decline of 24 mL/year. GWAS identified 67 variants associated with lung function decline (p<1e-5). rs150094594:C (β (SE): -15.4 (2.9) mL/year, p=1.5e-7), an intergenic variant, was replicated in one independent cohort (β (SE): -19.4 (7.2) mL/year; p=0.007). The meta-analysis of the three cohorts further confirmed the association of rs150094594 with lung function decline, with a pooled effect of β (SE): -15.9 (2.7) mL/year (p=3.9e-9). This study represents one of the largest GWAS on lung function decline and provides novel insights into its genetic architecture. Our findings suggest a meaningful role of individual variants on lung function decline, highlighting the genetic basis of respiratory ageing and disease.

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