Publications by authors named "Edwin K Silverman"

453 Publications

Multi-ethnic genome-wide and HLA association study of total serum IgE.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Department of Human Genetics, University of Chicago, Chicago, IL.

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.

Objective: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901).

Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article's Online Repository at www.jacionline.org.

Results: We identified six loci at genome-wide significance (P<5x10-9), including four loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, also identified in prior GWAS of atopic dermatitis and asthma. In the HLA allele association study, HLA-A*02:01 was associated with decreased tIgE (discovery P = 2x10, replication P = 5x10, discovery+replication P=4x10) and HLA-DQB1*03:02 was strongly associated with decreased tIgE in Hispanic/Latino ancestry populations (Hispanic/Latino discovery+replication P=8x10-8).

Conclusion: We performed the largest GWAS and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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http://dx.doi.org/10.1016/j.jaci.2021.09.011DOI Listing
September 2021

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.

Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

10 Year Follow-up of Lung Function, Respiratory Symptoms, and Functional Capacity in the COPDGene Study.

Ann Am Thorac Soc 2021 Aug 30. Epub 2021 Aug 30.

National Jewish Health, 2930, Denver, Colorado, United States.

Rationale: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The Genetic Epidemiology of COPD (COPDGene) study provides a unique cohort to examine these trajectories, and now 10 year follow-up data are available.

Objectives: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers.

Methods: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over 3 visits spanning approximately 10 years of follow-up. Change in post-bronchodilator forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ), and six-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline GOLD spirometry stages as well as by new 2019 COPDGene Classification.

Results: Mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD=9.2 years); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, as well as all groups categorized by 2019 COPDGene Classification, FEV1 decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10 year follow-up period. Current smokers exhibited a greater mean loss of FEV1 over the study period than former smokers for all groups except those with preserved ratio impaired spirometry (PRISm). For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, where former smokers had greater progression. However, this could be impacted by some current smokers with faster progression that had quit smoking and were dropped from analyses.

Conclusions: Progression in FEV1, SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV1 than former smokers, while SGRQ and 6MWD changes were more similar between current and former cigarette smokers.
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http://dx.doi.org/10.1513/AnnalsATS.202007-873OCDOI Listing
August 2021

Heterozygosity of the Alpha 1-Antitrypsin Pi*Z Allele and Risk of Liver Disease.

Hepatol Commun 2021 Aug 3;5(8):1348-1361. Epub 2021 Apr 3.

Department of Medicine Beth Israel Deaconess Medical Center Boston MA USA.

The serpin family A member 1 () Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1-antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population-based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital-based cohort. We also examined variants associated with liver disease and assessed for gene-gene and gene-environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53;  = 1.1×10); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8;  = 1.8 × 10). The OR for cirrhosis of the Z allele was comparable to that of well-established genetic variants, including patatin-like phospholipase domain containing 3 () I148M (OR, 1.48;  = 1.1 × 10) and transmembrane 6 superfamily member 2 () E167K (OR, 1.34;  = 2.6 × 10). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT;  = = 4.6 × 10), aspartate aminotransferase (AST;  = 2.2 × 10), alkaline phosphatase ( = 3.3 × 10), gamma-glutamyltransferase ( = 1.2 × 10), and total bilirubin ( = 6.4 × 10); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT ( interaction = 0.021) and AST ( interaction = 0.0040), suggesting a gene-environment interaction. Finally, we demonstrated genetic interactions between variants in , and hydroxysteroid 17-beta dehydrogenase 13 (); there was no evidence of epistasis between the Z allele and these variants. Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
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http://dx.doi.org/10.1002/hep4.1718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369947PMC
August 2021

A genome-wide association study of quantitative computed tomographic emphysema in Korean populations.

Sci Rep 2021 Aug 17;11(1):16692. Epub 2021 Aug 17.

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.

Emphysema is an important feature of chronic obstructive pulmonary disease (COPD). Genetic factors likely affect emphysema pathogenesis, but this question has predominantly been studied in those of European ancestry. In this study, we sought to determine genetic components of emphysema severity and characterize the potential function of the associated loci in Korean population. We performed a genome-wide association study (GWAS) on quantitative emphysema in subjects with or without COPD from two Korean COPD cohorts. We investigated the functional consequences of the loci using epigenetic annotation and gene expression data. We also compared our GWAS results with an epigenome-wide association study and previous differential gene expression analysis. In total, 548 subjects (476 [86.9%] male) including 514 COPD patients were evaluated. We identified one genome-wide significant SNP (P < 5.0 × 10), rs117084279, near PIBF1. We identified an additional 57 SNPs (P < 5.0 × 10) associated with emphysema in all subjects, and 106 SNPs (P < 5.0 × 10) in COPD patients. Of these candidate SNPs, 2 (rs12459249, rs11667314) near CYP2A6 were expression quantitative trait loci in lung tissue and a SNP (rs11214944) near NNMT was an expression quantitative trait locus in whole blood. Of note, rs11214944 was in linkage disequilibrium with variants in enhancer histone marks in lung tissue. Several genes near additional SNPs were identified in our previous EWAS study with nominal level of significance. We identified a novel SNP associated with quantitative emphysema on CT. Including the novel SNP, several candidate SNPs in our study may provide clues to the genetic etiology of emphysema in Asian populations. Further research and validation of the loci will help determine the genetic factors for the development of emphysema.
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http://dx.doi.org/10.1038/s41598-021-95887-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371078PMC
August 2021

Hedgehog interacting protein-expressing lung fibroblasts suppress lymphocytic inflammation in mice.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Channing Division of Network Medicine, and.

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and characterized by chronic inflammation in vulnerable individuals. However, it is unknown how genetic factors may shape chronic inflammation in COPD. To understand how hedgehog interacting protein, encoded by HHIP gene identified in the genome-wide association study in COPD, plays a role in inflammation, we utilized Hhip+/- mice that present persistent inflammation and emphysema upon aging similar to that observed in human COPD. By performing single-cell RNA sequencing of the whole lung from mice at different ages, we found that Hhip+/- mice developed a cytotoxic immune response with a specific increase in killer cell lectin-like receptor G1-positive CD8+ T cells with upregulated Ifnγ expression recapitulating human COPD. Hhip expression was restricted to a lung fibroblast subpopulation that had increased interaction with CD8+ T lymphocytes in Hhip+/- compared with Hhip+/+ during aging. Hhip-expressing lung fibroblasts had upregulated IL-18 pathway genes in Hhip+/- lung fibroblasts, which was sufficient to drive increased levels of IFN-γ in CD8+ T cells ex vivo. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.
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http://dx.doi.org/10.1172/jci.insight.144575DOI Listing
September 2021

Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors.

BMC Pulm Med 2021 Jul 14;21(1):235. Epub 2021 Jul 14.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied.

Methods: We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy.

Results: In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41-8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09-1.49), male sex (OR 3.60, CI 2.20-5.90), non-Hispanic white race (OR 3.33, CI 1.71-6.50), current smoking (OR 2.55, CI 1.49-4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38-8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05-0.35) and nocturnal (OR 0.46, CI 0.21-0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center.

Conclusions: In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.
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http://dx.doi.org/10.1186/s12890-021-01585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278596PMC
July 2021

An Integrative Genomic Strategy Identifies sRAGE as a Causal and Protective Biomarker of Lung Function.

Chest 2021 Jul 6. Epub 2021 Jul 6.

Framingham Heart Study, Framingham, MA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Background: There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease.

Study Question: Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function?

Study Design And Methods: Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits.

Results: Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function.

Interpretation: sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.
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http://dx.doi.org/10.1016/j.chest.2021.06.053DOI Listing
July 2021

Genetic variation in the mitochondrial glycerol-3-phosphate acyltransferase is associated with liver injury.

Hepatology 2021 Jul 3. Epub 2021 Jul 3.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Most of the genetic basis of chronic liver disease remains undiscovered. To identify novel genetic loci that modulate the risk of liver injury, we performed genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome-wide significance (P<5x10 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol-3-phosphate acyltransferase (GPAM rs10787429) associated with increased levels of ALT (P=1.4x10 ), AST (P=3.6x10 ), ALP (P=9.5x10 ) and total bilirubin (P=2.9x10 ). This common genetic variant was also associated with an allele dose-dependent risk of alcoholic liver disease (OR 1.34, P=2.6x10 ) and fatty liver disease (OR 1.18, P=5.8x10 ) by ICD-10 codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST (P-interaction=7.1x10 and 3.95x10 , respectively), as well as between GPAM rs10787429 and weekly alcohol consumption in association with ALT, AST, and alcoholic liver disease (P-interaction=4.0x10 , 1.6x10 and 1.3x10 , respectively). Unlike previously described genetic variants that are associated with an increased risk of liver injury but confer a protective effect on circulating lipids, GPAM rs10787429 was associated with an increase in total cholesterol (P=2.0x10 ), LDL cholesterol (P=2.0x10 ), and HDL cholesterol (P=6.6x10 ). Single-cell RNA sequencing data demonstrated hepatocyte-predominant expression of GPAM in cells that co-express genes related to VLDL production (P=9.4x10 ). In conclusion, genetic variation in GPAM is associated with susceptibility to liver injury. GPAM may represent a new therapeutic target in chronic liver disease.
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http://dx.doi.org/10.1002/hep.32038DOI Listing
July 2021

Connecting COPD GWAS genes: FAM13A controls TGFβ2 secretion by modulating AP-3 transport.

Am J Respir Cell Mol Biol 2021 Jun 24. Epub 2021 Jun 24.

Brigham and Women's Hospital, 1861, Channing Division of Network Medicine, Boston, Massachusetts, United States;

Chronic Obstructive Pulmonary Disease (COPD) is a common, complex disease and a major cause of morbidity and mortality. Although multiple genetic determinants of COPD have been implicated by genome-wide association studies (GWAS), the pathophysiologic significance of these associations remains largely unknown. From a COPD protein-protein interaction network module, we selected a network path between two COPD GWAS genes for validation studies: FAM13A-AP3D1-CTGF-TGFB2. We find that TGFβ2, FAM13A, and AP3D1 (but not CTGF) form a cellular protein complex. Functional characterization suggests that this complex mediates the secretion of TGFβ2 through an AP-3-dependent pathway, with FAM13A acting as a negative regulator by targeting a late stage of this transport that involves the dissociation of coat-cargo interaction. Moreover, we find that TGFβ2 is a transmembrane protein that engages the AP-3 complex for delivery to the late endosomal compartments for subsequent secretion through exosomes. These results identify a pathophysiologic context that unifies the biological network role of two COPD GWAS proteins and reveal novel mechanisms of cargo transport through an intracellular pathway.
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http://dx.doi.org/10.1165/rcmb.2021-0016OCDOI Listing
June 2021

Genome-wide association analysis of COVID-19 mortality risk in SARS-CoV-2 genomes identifies mutation in the SARS-CoV-2 spike protein that colocalizes with P.1 of the Brazilian strain.

Genet Epidemiol 2021 10 22;45(7):685-693. Epub 2021 Jun 22.

Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome-wide association studies (GWAS), we looked at the association between whole-genome sequencing (WGS) data of the virus and COVID-19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single-stranded SARS-CoV-2 genomes of COVID-19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome-wide significance (p values of 4.09e-09 and 4.41e-23, respectively), though only 25,088 bp remained significant in follow-up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e-13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow-up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real-time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.
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http://dx.doi.org/10.1002/gepi.22421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426743PMC
October 2021

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics.

Nat Commun 2021 05 25;12(1):3152. Epub 2021 May 25.

Department of Biostatistics, Columbia University, New York, NY, USA.

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.
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http://dx.doi.org/10.1038/s41467-021-22889-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149672PMC
May 2021

Relationship between rheumatoid arthritis and pulmonary function measures on spirometry in the UK Biobank.

Arthritis Rheumatol 2021 May 13. Epub 2021 May 13.

Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.

Objective: We investigated the independent relationship of rheumatoid arthritis (RA) with type and severity of pulmonary patterns on spirometry compared to general population controls.

Methods: This cross-sectional study investigated the association of RA and pulmonary function measures on spirometry among subjects who had spirometry performed for research purposes in the UK Biobank. RA cases were identified by self-report and current DMARD/glucocorticoid use. General population controls denied RA. Outcomes included continuous % predicted forced expiratory volume in 1 second (FEV ) and forced vital capacity (FVC), type of spirometric pattern (restrictive or obstructive), and severity. We used multivariable regression to estimate the effects of RA cases versus controls, adjusting for age, sex, body mass index (BMI), and smoking status/pack-years.

Results: Among 350,776 analyzed subjects with spirometry performed (mean age 56.3 years, 55.8% female, and 45.5% ever smokers), we identified 2,008 cases of treated RA. In multivariable analyses, RA was associated with lower % predicted FEV (β -2.93, 95%CI -3.63,-2.24), % predicted FVC (β -2.08, 95%CI -2.72,-1.45), and FEV /FVC (β -0.008, 95%CI -0.010,-0.005) than controls. RA was associated with restrictive (OR 1.36, 95%CI 1.21,1.52) and obstructive (OR 1.21, 95%CI 1.07,1.37) patterns independent of confounders. RA had the strongest associations for severe restrictive and obstructive patterns.

Conclusion: RA was associated with increased odds of restrictive and obstructive patterns, and this relationship was not explained by confounders including smoking. In addition to restrictive lung disease, clinicians should also be aware that airflow obstruction may be a pulmonary manifestation of RA.
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http://dx.doi.org/10.1002/art.41791DOI Listing
May 2021

A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 07 28;321(1):L130-L143. Epub 2021 Apr 28.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B () splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (), a gene involved in regulating cell proliferation, were associated with COPD (both < 0.0001). The Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
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http://dx.doi.org/10.1152/ajplung.00009.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321852PMC
July 2021

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

Respir Res 2021 Apr 27;22(1):127. Epub 2021 Apr 27.

Research and Development, GlaxoSmithKline, Collegeville, PA, USA.

Background: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.

Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).

Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log-transformed sRAGE was associated with 105 ± 22 mL lower FEV and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.

Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
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http://dx.doi.org/10.1186/s12931-021-01686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076883PMC
April 2021

Chromatin Landscapes of Human Lung Cells Predict Potentially Functional Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Variants.

Am J Respir Cell Mol Biol 2021 07;65(1):92-102

Channing Division of Network Medicine and.

Genome-wide association studies (GWASs) have identified dozens of loci associated with risk of chronic obstructive pulmonary disease (COPD). However, identifying the causal variants and their functional role in the appropriate cell type remains a major challenge. We aimed to identify putative causal variants in 82 GWAS loci associated with COPD susceptibility and predict the regulatory impact of these variants in lung-cell types. We used an integrated approach featuring statistical fine mapping, open chromatin profiling, and machine learning to identify functional variants. We generated chromatin accessibility data using the Assay for Transposase-Accessible Chromatin with High-Throughput Sequencing (ATAC-seq) for human primary lung-cell types implicated in COPD pathobiology. We then evaluated the enrichment of COPD risk variants in lung-specific open chromatin regions and generated cell type-specific regulatory predictions for >6,500 variants corresponding to 82 COPD GWAS loci. Integration of the fine-mapped variants with lung open chromatin regions helped prioritize 22 variants in putative regulatory elements with potential functional effects. Comparison with functional predictions from 222 Encyclopedia of DNA Elements (ENCODE) cell samples revealed cell type-specific regulatory effects of COPD variants in the lung epithelium, endothelium, and immune cells. We identified potential causal variants for COPD risk by integrating fine mapping in GWAS loci with cell-specific regulatory profiling, highlighting the importance of leveraging the chromatin status in relevant cell types to predict the molecular effects of risk variants in lung disease.
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http://dx.doi.org/10.1165/rcmb.2020-0475OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320120PMC
July 2021

Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside.

Clin Epigenetics 2021 Mar 30;13(1):66. Epub 2021 Mar 30.

Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, Italy.

Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its' very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine.
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http://dx.doi.org/10.1186/s13148-021-01047-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010949PMC
March 2021

Rare deleterious germline variants and risk of lung cancer.

NPJ Precis Oncol 2021 Feb 16;5(1):12. Epub 2021 Feb 16.

Mayo Clinic College of Medicine, Scottsdale, AZ, USA.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.
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http://dx.doi.org/10.1038/s41698-021-00146-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887261PMC
February 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

DNA methylation perturbations may link altered development and aging in the lung.

Aging (Albany NY) 2021 01 19;13(2):1742-1764. Epub 2021 Jan 19.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before. We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project. We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue. DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.
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http://dx.doi.org/10.18632/aging.202544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880367PMC
January 2021

Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort.

Eur Respir J 2021 03 25;57(3). Epub 2021 Mar 25.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.

Rationale: There are no validated measures of disease activity in COPD. Since "active" disease is expected to have worse outcomes ( mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality.

Methods: We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component.

Results: Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV, inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure.

Conclusions: In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements.
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http://dx.doi.org/10.1183/13993003.01339-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991608PMC
March 2021

Relative contributions of family history and a polygenic risk score on COPD and related outcomes: COPDGene and ECLIPSE studies.

BMJ Open Respir Res 2020 11;7(1)

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

Introduction: Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown.

Methods: We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses.

Results: In COPDGene, family history and PRS were significantly associated with COPD in a single model (P <0.0001; P<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs.

Conclusion: Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.
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http://dx.doi.org/10.1136/bmjresp-2020-000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689586PMC
November 2020

Epigenetics and pulmonary diseases in the horizon of precision medicine: a review.

Eur Respir J 2021 06 10;57(6). Epub 2021 Jun 10.

Dept of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, Italy

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with COPD, asthma and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also regulated epigenetically and potentially participate in disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individual's susceptibility to COPD, asthma and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, provides insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma and PAH. Epigenetic modifications may have clinical applications as noninvasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multistage transition from a "pre-disease" to "disease" state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management.We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.
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http://dx.doi.org/10.1183/13993003.03406-2020DOI Listing
June 2021

Characterization of a COPD-Associated Functional Splicing Genetic Variant in Human Lung Tissue via Long-Read Sequencing.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Genome-wide association studies (GWAS) have identified over 80 loci that are associated with COPD and emphysema, however for most of these loci the causal variant and gene are unknown. Here, we utilize lung splice quantitative trait loci (sQTL) data from the Genotype-Tissue Expression project (GTEx) and short read sequencing data from the Lung Tissue Research Consortium (LTRC) to characterize a locus in nephronectin ( ) associated with COPD case-control status and lung function. We found that the rs34712979 variant is associated with alternative splice junction use in , specifically for the junction connecting the 2nd and 4th exons (chr4:105898001-105927336) (p=4.02×10 ). This association colocalized with GWAS data for COPD and lung spirometry measures with a posterior probability of 94%, indicating that the same causal genetic variants in underlie the associations with COPD risk, spirometric measures of lung function, and splicing. Investigation of short read sequencing revealed that rs34712979 creates a cryptic splice acceptor site which results in the inclusion of a 3 nucleotide exon extension, coding for a serine residue near the N-terminus of the protein. Using Oxford Nanopore Technologies (ONT) long read sequencing we identified 13 isoforms, 6 of which are predicted to be protein coding. Two of these are full length isoforms which differ only in the 3 nucleotide exon extension whose occurrence differs by genotype. Overall, our data indicate that rs34712979 modulates COPD risk and lung function by creating a novel splice acceptor which results in the inclusion of a 3 nucelotide sequence coding for a serine in the nephronectin protein sequence. Our findings implicate splicing in contributing to COPD risk, and identify a novel serine insertion in the nephronectin protein that warrants further study.
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http://dx.doi.org/10.1101/2020.10.20.20203927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654922PMC
November 2020

Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease.

Am J Epidemiol 2021 05;190(5):875-885

Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008-2010) and SpiroMeta Consortium (multiple countries, 1947-2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.
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http://dx.doi.org/10.1093/aje/kwaa227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096488PMC
May 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020
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