Background: While low body mass index (BMI) is associated with emphysema and obesity is associated with airway disease in chronic obstructive pulmonary disease (COPD), the underlying mechanisms are unclear. Methods: We aggregated genetic variants from population-based genome-wide association studies to generate a polygenic score of BMI (PGSBMI). We calculated this score for participants from COPD-enriched and community-based cohorts and examined associations with automated quantification and visual interpretation of computed tomographic emphysema and airway wall thickness (AWT). We summarized the results using meta-analysis. Results: In the random-effects meta-analyses combining results of all cohorts (n=16,349), a standard deviation increase of the PGSBMI was associated with less emphysema as quantified by log-transformed percent of low attenuation areas ≤ 950 Hounsfield units (β= -0.062, p<0.0001) and 15th percentile value of lung density histogram (β=2.27, p<0.0001), and increased AWT as quantified by the square root of wall area of a 10-mm lumen perimeter airway (β=0.016, p=0.0006) and mean segmental bronchial wall area percent (β=0.26, p=0.0013). For imaging characteristics assessed by visual interpretation, a higher PGSBMI was associated with reduced emphysema in both COPD-enriched cohorts (OR for a higher severity grade=0.89, p=0.0080) and in the community-based Framingham Heart Study (OR for the presence of emphysema=0.82, p=0.0034), and a higher risk of airway wall thickening in the COPDGene study (OR=1.17, p=0.0023). Conclusions: In individuals with and without COPD, a higher body mass index polygenic risk is associated with both quantitative and visual decreased emphysema and increased AWT, suggesting genetic determinants of BMI affect both emphysema and airway wall thickening.

MM received grant support from Bayer and consulting fees from Sitka, 2ndMD, TheaHealth, TriNetX, Verona Pharma, and Axon Advisors. BRC received grant support from Chiesi Farmaceutici, consulting and advisory fees from GlaxoSmithKline, AstraZeneca, Axios, Sanofi Aventis, and Vertex, and honoraria from Glaxo Smith Kline, AstraZeneca, Menarini, Chiesi Farmaceutici, and Regeneron. EKS received grant support from Northpond Laboratories and Bayer. PB received consulting fees from GlaxoSmithKline, AstraZeneca, and Sanofi, and lecture fees from Pfizer, GlaxoSmithKline, AstraZeneca, and Sanofi. BDH and MHC received grant support from Bayer.

MM is supported by K08 HL159318. BDH was supported by NIH U01 HL089856, R01 HL147148, and an Alpha-1 Foundation Grant. EKS is supported by NIH R01 HL152728, R01 HL147148, U01 HL089856, R01 HL133135, and P01 HL114501. MHC is supported by NIH R01 HL137927, R01 HL135142, R01 HL147148, and R01 HL089856. Funding information for individual studies can be found in the Supplementary File.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Each study was approved by the Institutional Review Boards at participating institutions, and all participants provided written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors