Copy number variants (CNVs) are structural genetic variants consisting of large DNA segments whose number varies between individuals. The importance of these large-scale gains and losses has only recently been recognized: CNVs are extremely common, represent a large proportion of the total genetic variation, and contribute substantially to phenotypic variation and disease susceptibility. Asthma affects over 17 million people in the U.S. and represents a significant cause of morbidity. Though the cumulative results of more than 20 genome-wide genetic surveys for asthma susceptibility loci have successfully identified several novel asthma genes, none of these prior studies have assessed the role of CNVs in the pathogenesis of asthma. In preliminary studies using a genome-wide, family-based screen of ~500,000 single nucleotide polymorphism genotypes in 400 families with asthma, our group has identified several genomic regions harboring known structural variation that are strongly associated with asthma susceptibility, including several containing previously identified asthma genes. From these preliminary data, we hypothesize that common structural genomic variants confer important susceptibility to asthma prevalence in multiple populations. We propose 4 Specific Aims to test this hypothesis.
In Specific Aim 1 we will perform a family-based genome-wide association study in non-Hispanic white families with childhood asthma using high-resolution CNV genotype data generated with Affymetrix SNP6.0 microarrays. We will then technically validate the top 20 asthma- associated CNV regions identified using high-density oligonucleotide arrays and quantitative PCR methods.
In Specific Aim 2, we will replicate these associations in three independent asthma cohorts (total sample size ~6000 subjects), including Hispanic white and non-Hispanic black populations.
In Specific Aim 3 we will sequence candidate genes and perform follow-up SNP genotyping and association testing in the asthma cohorts to identify asthma-related nucleotide variation in 2 replicated asthma-associated CNV regions.
In Specific Aim 4 we will evaluate the impact of asthma-associated CNVs on mRNA gene expression and target protein expression levels for candidate genes residing within or near the asthma-associated CNVs in 180 asthmatics. This project has high potential to identify novel molecular targets critical to the pathobiology of asthma for therapeutic targeting.

Public Health Relevance

Structural genetic variants consist of large DNA segments whose number varies between individuals. This project aims to identify structural genetic variation that contributes to the development of asthma. We propose to conduct a genome-wide survey for such variation in a cohort of childhood asthmatics, with follow-up characterization of these regions and replication studies in populations representing the three major ethnic groups in the United States. Defining the genetic determinants of asthma will ultimately lead to the development of novel therapies and diagnostic tests.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093076-03
Application #
7841725
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Banks-Schlegel, Susan P
Project Start
2008-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$831,505
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Lawrence, Michael; Huber, Wolfgang; Pages, Herve et al. (2013) Software for computing and annotating genomic ranges. PLoS Comput Biol 9:e1003118
Rogers, A J; Chu, J-H; Darvishi, K et al. (2013) Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility. Clin Exp Allergy 43:455-62
Rogers, A J; Brasch-Andersen, C; Ionita-Laza, I et al. (2009) The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma. Clin Exp Allergy 39:1721-9