Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function
National Institutes of Health1, Erasmus University Rotterdam2, Boston University3, University of Washington4, University of North Carolina at Chapel Hill5, Ghent University6, Columbia University7, University of South Florida8, Group Health Cooperative9, Cedars-Sinai Medical Center10, Johns Hopkins University11, University of Texas Health Science Center at Houston12, University of Arizona13
TL;DR: This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study, and identified eight loci associated with FEV1/FVC and one locus at or near genome-wide significance in theCHARGE Consortium dataset.
Abstract: Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
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TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Abstract: A b s t r ac t Background Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. Methods We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. Results We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10 −9 ); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10 −14 ); rs1342326 on chromosome 9, flanking IL33 (P = 9×10 −10 ); rs744910 on chromosome 15 in SMAD3 (P = 4×10 −9 ); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10 −8 ). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10 −23 ). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Conclusions Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
1,764 citations
01 Jan 2014
1,464 citations
TL;DR: The rationale of the study and its design is given, and a summary of the major findings and an update of the objectives and methods are presented.
Abstract: The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
1,448 citations
TL;DR: The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.
Abstract: Van Eerdewegh P, Little RD, Dupuis J, et al Nature 2002;418:426–430
To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma
Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma
A genetic linkage analysis was performed for current asthma and BHR Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma Novel genes of interest were …
1,002 citations
TL;DR: The main cause is smoking tobacco, but other factors have been identified as mentioned in this paper, such as genetic determinants, lung growth, and environmental stimuli, which is further aggravated by exacerbations, particularly in patients with severe disease.
855 citations
References
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TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
26,280 citations
"Meta-analyses of genome-wide associ..." refers methods in this paper
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University of Manchester1, University of Barcelona2, St George's Hospital3, University of Marburg4, University of Texas Health Science Center at San Antonio5, Imperial College London6, University of Modena and Reggio Emilia7, University of Michigan8, Hokkaido University9, University of British Columbia10
TL;DR: It is recommended that spirometry is required for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation.
Abstract: Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.
17,023 citations
TL;DR: This research presents a novel and scalable approach called “Standardation of LUNG FUNCTION TESTing” that combines “situational awareness” and “machine learning” to solve the challenge of integrating nanofiltration into the energy system.
Abstract: [⇓][1]
SERIES “ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING”
Edited by V. Brusasco, R. Crapo and G. Viegi
Number 2 in this Series
[1]: #F13
13,426 citations
"Meta-analyses of genome-wide associ..." refers methods in this paper
...Spirometry was performed using a SpiroPro portable spirometer (Erich Jaeger GmbH...
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TL;DR: A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu.
Abstract: As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.
9,605 citations
"Meta-analyses of genome-wide associ..." refers background in this paper
...FLJ20184 encodes a hypothetical protein, according to several genome browsers including the UCSC Genome Browser (see URLs...
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TL;DR: This work describes a method that enables explicit detection and correction of population stratification on a genome-wide scale and uses principal components analysis to explicitly model ancestry differences between cases and controls.
Abstract: Population stratification—allele frequency differences between cases and controls due to systematic ancestry differences—can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker’s variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers. Population stratification—allele frequency differences between cases and controls due to systematic ancestry differences—can cause spurious associations in disease studies 1‐8 . Because the effects of stratification vary in proportion to the number of samples 9 , stratification will be an increasing problem in the large-scale association studies of the future, which will analyze thousands of samples in an effort to detect common genetic variants of weak effect. The two prevailing methods for dealing with stratification are genomic control and structured association 9‐14 . Although genomic control and structured association have proven useful in a variety of contexts, they have limitations. Genomic control corrects for stratification by adjusting association statistics at each marker by a uniform overall inflation factor. However, some markers differ in their allele frequencies across ancestral populations more than others. Thus, the uniform adjustment applied by genomic control may be insufficient at markers having unusually strong differentiation across ancestral populations and may be superfluous at markers devoid of such differentiation, leading to a loss in power. Structured association uses a program such as STRUCTURE 15 to assign the samples to discrete subpopulation clusters and then aggregates evidence of association within each cluster. If fractional membership in more than one cluster is allowed, the method cannot currently be applied to genome-wide association studies because of its intensive computational cost on large data sets. Furthermore, assignments of individuals to clusters are highly sensitive to the number of clusters, which is not well defined 14,16 .
9,387 citations
"Meta-analyses of genome-wide associ..." refers methods in this paper
...for any of the first ten principal components using EIGENSTRA...
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