Dataset Information

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

ABSTRACT:

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 <0·7 and FEV₁ <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

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.

Funding

US National Institutes of Health, Wellcome Trust.

SUBMITTER: Moll M

PROVIDER: S-EPMC7429152 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesThe irreversible airflow limitation characterised by chronic obstructive pulmonary disease (COPD) causes a decrease in the oxygen supply to the brain. The aim of the present study was to investigate brain structural damage in COPD.DesignRetrospective case-control study. Patients with COPD and healthy volunteers were recruited. The two groups were matched in age, gender and educational background.SettingA hospital and a number of communities: they are all located in southern Fujian province, China.Participants25 stable patients and 25 controls were enrolled from December 2009 to May 2011.MethodsUsing voxel-based morphometry and tract-based spatial statistics based on MRI to analyse grey matter (GM) density and white matter fractional anisotropy (FA), respectively, and a battery of neuropsychological tests were performed.ResultsPatients with COPD (vs controls) showed decreased GM density in the limbic and paralimbic structures, including right gyrus rectus, left precentral gyrus, bilateral anterior and middle cingulate gyri, bilateral superior temporal gyri, bilateral anterior insula extending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD (vs controls) had decreased FA values in the bilateral superior corona radiata, bilateral superior and inferior longitudinal fasciculus, bilateral optic radiation, bilateral lingual gyri, left parahippocampal gyrus and fornix. Lower FA values in these regions were associated with increased radial diffusivity and no changes of longitudinal diffusivity. Patients with COPD had poor performances in the Mini-Mental State Examination, figure memory and visual reproduction. GM density in some decreased regions in COPD had positive correlations with arterial blood Po(2), negative correlations with disease duration and also positive correlations with visual tasks.ConclusionThe authors demonstrated that COPD exhibited loss of regional GM accompanied by impairment of white matter microstructural integrity, which was associated with disease severity and may underlie the pathophysiological and psychological changes of COPD.