Bronchiectasis GWAS Highlights Candidate Targets Shared With COPD

Bronchiectasis appears to share genetic signals with chronic obstructive pulmonary disease (COPD), asthma, and chronic bronchitis, and a cross-ancestry genetic analysis of more than 1.8 million people identified new risk signals and several candidate drug targets.¹

Bronchiectasis is a chronic airway disease driven by a cycle of infection, inflammation, impaired mucus clearance, and structural lung damage. Its genetic roots have been studied far less than those of asthma or COPD, which limits the development of targeted therapies. The disease carries a heavy financial burden. A recent Medicare analysis found that beneficiaries with newly diagnosed non–cystic fibrosis bronchiectasis had a mean total fee-for-service spending of $8998 per person per month, with inpatient hospitalization accounting for $4968 of that amount.²

Brensocatib (Brinsupri; Insmed) became the first FDA-approved therapy for non–cystic fibrosis bronchiectasis in 2025, but treatment options remain limited.³ In the new study, published in the Journal of Translational Medicine, researchers aimed to refine the genetic architecture of bronchiectasis, prioritize candidate molecular targets, and define what it shares with related airway diseases.¹

SERPINA1, Immune Pathways Lead Bronchiectasis Genetic Signals

The researchers pooled genome-wide association study (GWAS) summary statistics from 6 biobank cohorts. The European-ancestry analysis drew on the UK Biobank, FinnGen, and the Million Veteran Program and included 11,795 cases and 1,304,979 controls. The East Asian-ancestry analysis drew on the China Kadoorie Biobank, the Taiwan Precision Medicine Initiative, and BioBank Japan and included 4235 cases and 536,162 controls. Combined, the trans-ancestry analysis covered 16,030 cases and 1,841,141 controls.¹ Cases were identified by diagnosis codes.

The team then used fine-mapping, Mendelian randomization, lung tissue gene expression analysis, and colocalization to narrow genetic hits down to likely effector genes and proteins.

The European analysis identified 5 lead signals, including a putatively novel locus near PTPN22. The East Asian analysis found 1 signal, located in the major histocompatibility complex (MHC) region. In the trans-ancestry analysis, the strongest association was rs28929474 at SERPINA1 (P = 2.19 × 10⁻¹⁶). SERPINA1 encodes α1-antitrypsin, a key inhibitor of neutrophil elastase. A deficiency of this inhibitor can tip the lung's protease balance toward airway damage.

At the protein level, AIF1 and WWP2 had strong support in Europeans, while HSPA1A and DXO emerged as exploratory candidates in East Asians. Lung tissue analyses also flagged CHP2 and FUBP1 in Europeans, both outside the MHC and both considered druggable. Variants near CHP2 have previously been linked to chronic Pseudomonas aeruginosa infection in cystic fibrosis and to Mycobacterium avium complex lung disease.

Bronchiectasis Shares Genetic Roots With COPD, Asthma

Bronchiectasis often overlaps with other airway diseases in clinical practice. The authors noted that European Bronchiectasis Registry data show 19.9% of patients meet criteria for bronchiectasis-COPD overlap and 31.0% have investigator-reported asthma.

The genetics were reflected in that overlap. In Europeans, bronchiectasis showed significant positive genetic correlations with chronic bronchitis (rg = 0.51), COPD (rg = 0.48), and asthma (rg = 0.41). In East Asians, only the correlation with chronic bronchitis was significant (rg = 0.77). However, the authors considered the chronic brinchitis analyses exploratory because case identification varied across cohorts and residual confounding by smoking could not be excluded.

Several shared genes stood out. SERPINA1 and SMAD3 linked bronchiectasis with both COPD and chronic bronchitis. CFTR was shared with COPD and asthma, and PHTF1 with asthma and chronic bronchitis. SMAD3, which may contribute to airway remodeling, had the most consistent support. Genetically predicted higher SMAD3 expression in whole blood was associated with a lower risk of bronchiectasis (OR, 0.75; false discovery rate = 0.025), and colocalization supported a shared causal signal.

"These findings support bronchiectasis as a genetically connected but biologically distinct component of the chronic airway disease spectrum and highlight candidate molecular targets that warrant further functional and therapeutic investigation," the study authors wrote.

The study was limited by smaller East Asian datasets, which limited statistical power, and diagnostic definitions varied across cohorts. Secondary causes of bronchiectasis, including cystic fibrosis, could not be fully excluded, and no independent replication cohort was available. The authors said the molecular and druggability findings should be considered hypothesis-generating.

Still, researchers noted that the SERPINA1 signal stands out. Its identification "provides population-level genetic support for the involvement of SERPINA1 in bronchiectasis susceptibility and reinforces the broader relevance of α1-antitrypsin biology beyond classical emphysema and COPD," they wrote.

References

1. Miao K, Li D, Cai S, Hong X. Cross-ancestry bronchiectasis GWAS meta-analysis and multi-omics integration prioritize candidate molecular targets. J Transl Med. Published online October 2026. doi:10.1186/s12967-026-09081-2

2. McCrear S. Non-CF bronchiectasis linked to high Medicare use and spending. AJMC. October 14, 2026. Accessed October 20, 2026. https://www.ajmc.com/view/non-cf-bronchiectasis-linked-to-high-medicare-use-and-spending

3. McCormick B. Brensocatib becomes first FDA-approved therapy for bronchiectasis. AJMC. August 12, 2025. Accessed October 20, 2026. https://www.ajmc.com/view/brensocatib-becomes-first-fda-approved-therapy-for-bronchiectasis