19 research outputs found
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 <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 subtyp
Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions.
Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers
Chronic obstructive pulmonary disease and related phenotypes:polygenic risk scores in population-based and case-control cohorts
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 1
<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.
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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies
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 <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
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 <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
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
Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions
Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers
Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by >/=2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies