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Original Article

Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility

  1. A. J. Rogers1,2,3,*,
  2. J.-H. Chu1,3,
  3. K. Darvishi3,4,
  4. I. Ionita-Laza5,
  5. H. Lehmann1,
  6. R. Mills6,
  7. C. Lee3,4,
  8. B. A. Raby1,2,3

Article first published online: 21 MAR 2013

DOI: 10.1111/cea.12060

Issue

Clinical & Experimental Allergy

Clinical & Experimental Allergy

Volume 43, Issue 4, pages 455–462, April 2013

Additional Information

How to Cite

A. J. Rogers, J.-H. Chu, K. Darvishi, I. Ionita-Laza, H. Lehmann, R. Mills, C. Lee, B. A. Raby. Clinical & Experimental Allergy 2013 (43) 455–462.

Author Information

  1. 1

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

  2. 2

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA

  3. 3

    Harvard Medical School, Boston, MA, USA

  4. 4

    Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

  5. 5

    Department of Biostatistics, Columbia University, New York, NY, USA

  6. 6

    Department of Computational Medicine and Bioinformatics and Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

* Correspondence:
Angela J. Rogers, Instructor in Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
E-mail: reajr@channing.harvard.edu

Publication History

  1. Issue published online: 21 MAR 2013
  2. Article first published online: 21 MAR 2013
  3. Accepted manuscript online: 15 NOV 2012 10:06AM EST
  4. Manuscript Accepted: 22 OCT 2012
  5. Manuscript Revised: 11 OCT 2012
  6. Manuscript Received: 15 AUG 2012

Funded by

  • NHLBI. Grant Number: R01 HL093076
  • NHLBI. Grant Numbers: N01 HR16049, R01 HL086601, U01 HL065899, P01 HL083069, K12HL08999, K12HL089990
  • National Institutes of Health and the NHLBI
  • National Institutes of Health

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Keywords:

  • association;
  • asthma genetics;
  • copy number variant;
  • NOS1;
  • polymorphism;
  • SERPINA3;
  • structural variant

Summary

Background

Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).

Objective

To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci.

Methods

We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV.

Results

Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma-candidate CNVs (range 1–29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.

Conclusions and Clinical Relevance

Although a substantial proportion of asthma-susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.

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