Genetic pleiotropy between pulmonary function and age-related traits: The Long Life Family Study

Background: Pulmonary function (PF) progressively declines with aging. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) are predictors of morbidity of pulmonary and cardiovascular diseases and all-cause mortality. In addition, reduced PF is associated with elevated chronic low-grade systemic inflammation, glucose metabolism, body fatness, and low muscle strength. It may suggest pleiotropic genetic effects between PF with these age-related factors.

Methods: We evaluated whether FEV1 and FVC share common pleiotropic genetic effects factors with interleukin-6, high-sensitivity C-reactive protein, body mass index, muscle (grip) strength, plasma glucose, and glycosylated hemoglobin in 3,888 individuals (age range: 26-106). We employed sex-combined and sex-specific correlated meta-analyses to test whether combining genome-wide association p-values from two or more traits enhances the ability to detect variants sharing effects on these correlated traits.

Results: We identified 32 loci for PF, including 29 novel pleiotropic loci associated with pulmonary function and (i) body fatness (CYP2U1/SGMS2), (ii) glucose metabolism (CBWD1/DOCK8 and MMUT/CENPQ), (iii) inflammatory markers (GLRA3/HPGD, TRIM9, CALN1, CTNNB1/ZNF621, GATA5/SLCO4A1/NTSR1, and NPVF/C7orf31/CYCS), and (iv) muscle strength (MAL2, AC008825.1/LINC02103, AL136418.1).

Conclusions: The identified genes/loci for PF and age-related traits suggest their underlying shared genetic effects, which can explain part of their phenotypic correlations. Integration of gene expression and genomic annotation data shows enrichment of our genetic variants in lung, blood, adipose, pancreas, and muscles, among others. Our findings highlight the critical roles of identified gene/locus in systemic inflammation, glucose metabolism, strength performance, PF, and pulmonary disease, which are involved in accelerated biological aging.