Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.Methods: We constructed a polygenic risk score using a genome wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75 0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.</div

Novel and previously identified BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in African ancestry discovery and replication samples, and European ancestry replication samples.

<p>Novel and previously identified BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in African ancestry discovery and replication samples, and European ancestry replication samples.</p

Additional novel BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in sex-stratified analyses of African ancestry discovery and replication samples.

<p>Additional novel BMI and WHR_adjBMI loci at <i>P</i> < 5×10⁻⁸ in sex-stratified analyses of African ancestry discovery and replication samples.</p

Identification of four independent LD blocks in the 8p23.1 region <i>(~3</i>.<i>3 MBs</i>).

<p>Identification of four independent LD blocks in the 8p23.1 region <i>(~3</i>.<i>3 MBs</i>).</p

Novel SNVs/Genes associated with BP traits in Multi-ancestry meta-analysis in combined Stage 1 and Stage 2.

<p>Novel SNVs/Genes associated with BP traits in Multi-ancestry meta-analysis in combined Stage 1 and Stage 2.</p

Novel SNVs/Genes associated with BP traits in European ancestry.

<p>Novel SNVs/Genes associated with BP traits in European ancestry.</p

Novel SNVs/Genes associated with BP traits from correlated meta-analysis in European ancestry in Stage 1.

<p>Novel SNVs/Genes associated with BP traits from correlated meta-analysis in European ancestry in Stage 1.</p

Potential novel SNVs/Genes associated with BP traits in African ancestry.

<p>Potential novel SNVs/Genes associated with BP traits in African ancestry.</p

Novel SNVs/Genes associated with BP traits in European ancestry.

<p>Novel SNVs/Genes associated with BP traits in European ancestry.</p