rs10808265 (PLXNA4): Lung Function Decline GWAS

Key takeaways

• rs10808265 is located near PLXNA4 (Plexin A4), a locus examined in a genome-wide study of age-related lung function decline.
• Genetic signals for lung function decline differed substantially between people with and without asthma, suggesting disease-specific pathways.
• No variant in the study reached conventional genome-wide significance, so all findings for this locus remain preliminary.
• Genes linked to how lung function declines over time appear distinct from those linked to baseline lung function levels.
• The discovery phase covered roughly 4,100 adults from three European cohorts, with replication in roughly 12,000 additional participants.

What the research says rs10808265 and the surrounding locus were among approximately 2.5 million genetic variants examined in a genome-wide association study (GWAS) -- a method that simultaneously scans variants across the entire genome -- investigating age-related decline in FEV1 (forced expiratory volume in the first second, the volume of air exhaled in one second) and in the FEV1/FVC ratio (FVC = forced vital capacity, the total air exhaled forcefully; this ratio gauges how much of lung capacity can be expelled quickly and is used to assess airway obstruction). Analyses were conducted separately for adults with asthma (approximately 1,441 in discovery, 1,160 in replication) and adults without asthma (approximately 2,677 in discovery, 10,858 in replication), and the top genetic signals differed substantially between these two groups. No SNP reached genome-wide significance in any analysis.

Reported associations

• FEV1 decline: This locus was evaluated among approximately 2.5 million variants for association with the rate of FEV1 decrease over a roughly 10-year follow-up, analyzed separately in asthmatics and non-asthmatics. No genome-wide significant association was established for any variant in the study.
• FEV1/FVC ratio decline: The study also examined associations with decline in this ratio, stratified by asthma status. No genome-wide significant association was identified in any group.

Evidence quality The discovery phase combined three European cohorts -- EGEA, SAPALDIA, and ECRHS -- totaling approximately 4,118 adults with standardized spirometry at two time points roughly 10 years apart. Thirty top loci were followed up in replication cohorts totaling approximately 12,018 additional adults drawn from ARIC, FHS, B58C, and a Dutch asthma study. Despite examining 2.5 million SNPs, none reached genome-wide significance for either lung function decline phenotype. The only replicated signal in the study was DLEU7 for FEV1 decline in non-asthmatics, which cleared replication only at a nominal threshold (discovery P = 4.8 x 10-6, replication P = 0.03), and sensitivity analyses pointed to a relation to growth. The top signal in asthmatics, TUSC3 for FEV1/FVC decline (P = 5.3 x 10-8 in discovery), did not replicate. The study authors concluded that the genetic architecture of longitudinal lung function decline is extensive and likely distinct from that of cross-sectional lung function, and that genetic determinants vary by asthma status. Evidence for this locus is preliminary, and no specific effect size for rs10808265 can be derived from the available study data.

Lifestyle considerations No lifestyle considerations on file for this variant.