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NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

ABSTRACT:

This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP).

The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

PROVIDER: phs000988 | dbGaP |

SECONDARY ACCESSION(S): PRJNA295246PRJNA295247

REPOSITORIES: dbGaP

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Project description:BACKGROUND: Evaluation of the airway transcriptome may reveal patterns of gene expression that are associated with clinical phenotypes of asthma. To define transcriptomic endotypes of asthma (TEA) we analyzed gene expression in induced sputum that correlate with phenotypes of disease. METHODS: Gene expression was measured in sputum of subjects with asthma using Affymetrix HuGene ST 1.0 microarrays. Unsupervised clustering analysis of genes in pathways selected from the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified TEA clusters. Clinical characteristics were compared and logistic regression analysis of matched blood samples defined an expression profile to determine the TEA cluster assignment in a cohort of children with asthma for validation. RESULTS: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower pre-bronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04), compared to the other TEA clusters. TEA cluster 2, the smallest cluster had the most subjects that were hospitalized for asthma (P = 0.04). Subjects in TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 x 10-06) and hospitalization (P = 0.01), respectively. CONCLUSIONS: Patterns of gene expression in the sputum and blood reveal TEA clusters that are associated with severe asthma phenotypes in children and adults. Gene expression was measured in sputum of subjects with asthma using Affymetrix HuGene ST 1.0 microarrays. Unsupervised clustering analysis of genes in pathways selected from the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified TEA clusters. Clinical characteristics were compared and logistic regression analysis of matched blood samples defined an expression profile to determine the TEA cluster assignment in a cohort of children with asthma for validation.

Project description:Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the M-bM-^@M-^\missing heritability problem.M-bM-^@M-^] Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complementary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility, as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility. 96 RNA samples were collected (1 subsequently excluded) from lymphoblastoid cell lines derived from Hutterite subjects chosen to represent the extremes of absolute lymphocyte count. The high and low absolute lymphocyte count groups were balanced with respect to age, gender, and relatedness.

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NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

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