Publications by authors named "Phuwanat Sakornsakolpat"

18 Publications

  • Page 1 of 1

A polygenic risk score for asthma in a large racially diverse population.

Clin Exp Allergy 2021 Aug 30. Epub 2021 Aug 30.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, Massachusetts, USA.

Background: Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes.

Objective: We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations.

Methods: We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire.

Results: For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)).

Conclusion: Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.
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http://dx.doi.org/10.1111/cea.14007DOI Listing
August 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

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

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

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

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

Lancet Respir Med 2020 07;8(7):696-708

Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.

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 (FEV and FEV/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 FEV/FVC <0·7 and FEV <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.
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http://dx.doi.org/10.1016/S2213-2600(20)30101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429152PMC
July 2020

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2020 03;201(5):564-574

Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. We identified and replicated three new genome-wide significant ( < 5 × 10) signals of association with IPF susceptibility (associated with altered gene expression of , , and ) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. The observation that decreased expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
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http://dx.doi.org/10.1164/rccm.201905-1017OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047454PMC
March 2020

DSP variants may be associated with longitudinal change in quantitative emphysema.

Respir Res 2019 Jul 19;20(1):160. Epub 2019 Jul 19.

Department of Epidemiology, Johns Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.

Background: Emphysema, characterized by lung destruction, is a key component of Chronic Obstructive Pulmonary Disease (COPD) and is associated with increased morbidity and mortality. Genome-wide association studies (GWAS) have identified multiple genetic factors associated with cross-sectional measures of quantitative emphysema, but the genetic determinants of longitudinal change in quantitative measures of emphysema remain largely unknown. Our study aims to identify genetic variants associated with longitudinal change in quantitative emphysema measured by computed tomography (CT) imaging.

Methods: We included current and ex-smokers from two longitudinal cohorts: COPDGene, a study of Non-Hispanic Whites (NHW) and African Americans (AA), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). We calculated annual change in two quantitative measures of emphysema based on chest CT imaging: percent low attenuation area (≤ - 950HU) (%LAA-950) and adjusted lung density (ALD). We conducted GWAS, separately in 3030 NHW and 1158 AA from COPDGene and 1397 Whites from ECLIPSE. We further explored effects of 360 previously reported variants and a lung function based polygenic risk score on annual change in quantitative emphysema.

Results: In the genome-wide association analysis, no variants achieved genome-wide significance (P < 5e-08). However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (β (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (β (SE) = - 0.06 (0.02), P = 2.88e-03). A lung function based polygenic risk score was associated with annual change in %LAA-950 (P = 4.03e-02) and with baseline measures of quantitative emphysema (P < 1e-03) and showed a trend toward association with annual change in ALD (P = 7.31e-02).

Conclusions: DSP variants may be associated with longitudinal change in quantitative emphysema. Additional investigation of the DSP gene are likely to provide further insights into the disease progression in emphysema and COPD.

Trial Registration: Clinicaltrials.gov Identifier: NCT00608764 , NCT00292552 .
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http://dx.doi.org/10.1186/s12931-019-1097-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642569PMC
July 2019

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene.

PLoS Genet 2019 07 3;15(7):e1008229. Epub 2019 Jul 3.

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

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 55.3% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.
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http://dx.doi.org/10.1371/journal.pgen.1008229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634423PMC
July 2019

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Nat Genet 2019 03 25;51(3):494-505. Epub 2019 Feb 25.

Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, South Korea.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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http://dx.doi.org/10.1038/s41588-018-0342-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546635PMC
March 2019

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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http://dx.doi.org/10.1038/s41588-018-0321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397078PMC
March 2019

Genome-Wide Association Analysis of Single-Breath Dl.

Am J Respir Cell Mol Biol 2019 05;60(5):523-531

1 Channing Division of Network Medicine and.

Dl is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of Dl could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of Dl using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for Dl in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and Dl. We estimated the SNP-based heritability of Dl in the European ancestry white population to be 22% ( = 0.0004). We identified three genome-wide significant associations with Dl: variants near , , and loci ( < 5 × 10). In addition, 12 loci were suggestively associated with Dl in European ancestry white ( < 1 × 10 in the combined analysis and  < 0.05 in both COPDGene and GenKOLS), including variants near , , , , , , , , , , , and . Some Dl-associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, , , , and were associated with Dl ( < 0.001). We identified several genetic loci that were significantly associated with Dl and characterized effects of known COPD-associated loci on Dl. These results could lead to better understanding of the heterogeneous nature of COPD.
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http://dx.doi.org/10.1165/rcmb.2018-0384OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503619PMC
May 2019

Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution.

Am J Respir Cell Mol Biol 2019 04;60(4):388-398

1 Channing Division of Network Medicine.

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P < 0.05), with the strongest enrichment observed in CD4, CD8, and regulatory T cells. We selected a putative causal variant, rs7962469, associated with ACVR1B expression in lung tissue for additional functional investigation, and reporter assays confirmed allele-specific regulatory activity for this variant in human bronchial epithelial and Jurkat immune cell lines. ACVR1B expression levels exhibit a nominally significant association with emphysema distribution. EABD-associated loci are preferentially enriched in regulatory elements of multiple cell types, most notably T-cell subsets. Multiple EABD loci colocalize to regulatory elements that are active across multiple tissues and cell types, and functional analyses confirm the presence of an EABD-associated functional variant that regulates ACVR1B expression, indicating that transforming growth factor-β signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
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http://dx.doi.org/10.1165/rcmb.2018-0110OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444627PMC
April 2019

GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort.

J Affect Disord 2019 01 7;243:16-22. Epub 2018 Sep 7.

Department of Psychiatry, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address:

Background: Large sample GWAS is needed to identify genetic factors associated with depression. This study used genome-wide genotypic and phenotypic data from the COPDGene study to identify genetic risk factors for depression.

Methods: Data were from 9716 COPDGene subjects with ≥10 pack-year history. Depression was defined as antidepressant use and/or a HADS depression subscale score ≥8. Non-Hispanic White (6576) and African-American (3140) subsets were analyzed. A GWAS pipeline identified SNPs associated with depression in each group. Network analysis software analyzed gene interactions through common biological pathways, genetic interactions, and tissue-specific gene expression.

Results: The mean age was 59.4 years (SD 9.0) with 46.5% female subjects. Depression was in 24.7% of the NHW group (1622) and 12.5% of the AA group (391). No SNPs had genome-wide significance. One of the top SNPs, rs12036147 (p = 1.28 × 10), is near CHRM3. Another SNP was near MDGA2 (rs17118176, p = 3.52 × 10). Top genes formed networks for synaptic transmission with a statistically significant level of more co-expression in brain than other tissues, particularly in the basal ganglia (p = 1.00 × 10).

Limitations: Limitations included a depression definition based on antidepressant use and a limited HADS score subgroup, which could increase false negatives in depressed patients not on antidepressants. Antidepressants used for smoking cessation in non-depressed patients could lead to false positives.

Conclusions: Systems biology analysis identified statistically significant pathways whereby multiple genes influence depression. The gene set pathway analysis and COPDGene data can help investigate depression in future studies.
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http://dx.doi.org/10.1016/j.jad.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186181PMC
January 2019

Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.

Am J Respir Cell Mol Biol 2018 11;59(5):614-622

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

Genome-wide association studies have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome, as compared with genotyping arrays or exome sequencing. We hypothesized that WGS in subjects with severe COPD and smoking control subjects with normal pulmonary function would allow us to identify novel genetic determinants of COPD. We sequenced 821 patients with severe COPD and 973 control subjects from the COPDGene and Boston Early-Onset COPD studies, including both non-Hispanic white and African American individuals. We performed single-variant and grouped-variant analyses, and in addition, we assessed the overlap of variants between sequencing- and array-based imputation. Our most significantly associated variant was in a known region near HHIP (combined P = 1.6 × 10); additional variants approaching genome-wide significance included previously described regions in CHRNA5, TNS1, and SERPINA6/SERPINA1 (the latter in African American individuals). None of our associations were clearly driven by rare variants, and we found minimal evidence of replication of genes identified by previously reported smaller sequencing studies. With WGS, we identified more than 20 million new variants, not seen with imputation, including more than 10,000 of potential importance in previously identified COPD genome-wide association study regions. WGS in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1. Larger sample sizes will be needed to identify associated variants in novel regions of the genome.
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http://dx.doi.org/10.1165/rcmb.2018-0088OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236690PMC
November 2018

Integrative genomics identifies new genes associated with severe COPD and emphysema.

Respir Res 2018 03 22;19(1):46. Epub 2018 Mar 22.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA.

Background: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes.

Methods: We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization.

Results: We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation.

Conclusions: An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci.

Trial Registration: NCT00608764 , Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552 , Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered).
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http://dx.doi.org/10.1186/s12931-018-0744-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863845PMC
March 2018

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations.

Hum Mol Genet 2018 05;27(10):1819-1829

Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Quebec City, QC, Canada.

Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative trait loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied. First, the lung eQTL dataset which included whole-genome gene expression and genotyping data from 1038 individuals. Second, the largest COPD GWAS to date from the International COPD Genetics Consortium (ICGC) with 13 710 cases and 38 062 controls. Methods that integrated GWAS with eQTL signals including transcriptome-wide association study (TWAS), colocalization and Mendelian randomization-based (SMR) approaches were used to map causality genes, i.e. genes with the strongest evidence of being the functional effector at specific loci. These methods were applied at the genome-wide level and at COPD risk loci derived from the GWAS literature. Replication was performed using lung data from GTEx. We collated 129 non-overlapping risk loci for COPD from the GWAS literature. At the genome-wide scale, 12 new COPD candidate genes/loci were revealed and six replicated in GTEx including CAMK2A, DMPK, MYO15A, TNFRSF10A, BTN3A2 and TRBV30. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci and 23 of them were replicated in GTEx. Mapping candidate causal genes in lung tissue represents an important contribution to the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.
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Source
http://dx.doi.org/10.1093/hmg/ddy091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932553PMC
May 2018
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