Genome-wide Association Studies From Four Cohorts Reveal Multiple Novel Loci Related To Pulmonary Function

Hancock, Dana B.; Eijgelsheim, Mark; Wilk, Jemma B.; Gharib, Sina A.; Loehr, Laura R.; Marciante, Kristin D.; Franceschini, Nora; Durme, Yannick M. van; Chen, Ting-hsu; Barr, R. Graham; Schabath, Matthew B.; Couper, David; Brusselle, Guy; Psaty, Bruce M.; Duijn, Cornelia M. van; Rotter, Jerome I.; Uitterlinden, André G.; Hofman, Albert; Punjabi, Naresh M.; Rivadeneira, Fernando; Morrison, Alanna C.; Enright, Paul; North, Kari E.; Heckbert, Susan R.; Lumley, Thomas; Stricker, Bruno H.; O’Connor, George T.; London, Stephanie J.

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5374

Cited by 10 publications

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“…Emphysema, defined as parenchymal destruction and enlargement of distal airspaces in the absence of fibrosis, can be present in individuals with COPD and in smokers with normal spirometry. Emphysema is partly determined by genetics, with an estimated heritability of approximately 30% (3); and genomewide association studies (GWAS) have identified genetic determinants associated with COPD susceptibility (4-6), spirometric measures (7)(8)(9), and emphysema (10,11).…”

mentioning

confidence: 99%

Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

Castaldi

Cho

Estépar

et al. 2014

Am J Respir Crit Care Med

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Rationale: Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown.Objectives: To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci.Methods: Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines.Measurements and Main Results: Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cellcell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P , 5 3 10 26 ) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts.Conclusions: This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment.

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confidence: 99%

Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

Castaldi

Cho

Estépar

et al. 2014

Am J Respir Crit Care Med

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“…Candidategene studies identified potential susceptibility loci for COPD or COPD-related phenotypes in inflammatory, oxidant-antioxidant, and protease-antiprotease gene pathways, a few of which have been subsequently replicated using genome-wide approaches (e.g., matrix metalloproteinase 12, MMP12) (6)(7)(8). Over the last 6 years, GWAS have identified multiple susceptibility genes for COPD or its intermediate phenotypes (e.g., lung function), confirming the multifactorial etiology of most cases (8)(9)(10).…”

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confidence: 86%

The Advent of High-Throughput Sequencing Studies of Chronic Obstructive Pulmonary Disease

Ortega

Celedón

2016

Am J Respir Crit Care Med

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“…Garnering strength in consistency of signal across the various ethnic groups (NHWs, African Americans, Hispanics, and Chinese), two distinct loci, SNRPF and PPT2, were identified as key determinants of percent emphysema defined as lung regions below 2950 Hounsfield units on computed tomography scan. Both loci were previously implicated in GWAS of individuals with European ancestry as determinants of pulmonary function (12,13). Correcting for FEV 1 /FVC, the authors show that these single-nucleotide polymorphisms (SNPs) likely act directly on emphysema with consequent effects on lung function, providing valuable insight into potential biological mechanism of action.…”

Section: Looking For Signal In All the Right Placesmentioning

confidence: 98%

On the Threshold from Genome-Wide Association Studies to Whole-Genome Sequencing. Looking for Signal in All the Right Places

Hansel¹,

Mathias²

2014

Am J Respir Crit Care Med

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Genome-wide Association Studies From Four Cohorts Reveal Multiple Novel Loci Related To Pulmonary Function

Cited by 10 publications

References 0 publications

Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

The Advent of High-Throughput Sequencing Studies of Chronic Obstructive Pulmonary Disease

On the Threshold from Genome-Wide Association Studies to Whole-Genome Sequencing. Looking for Signal in All the Right Places

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