Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility
Article first published online: 21 MAR 2013
© 2012 Blackwell Publishing Ltd
Clinical & Experimental Allergy
Volume 43, Issue 4, pages 455–462, April 2013
How to Cite
Clinical & Experimental Allergy 2013 (43) 455–462., , , , , , , .
- Issue published online: 21 MAR 2013
- Article first published online: 21 MAR 2013
- Accepted manuscript online: 15 NOV 2012 10:06AM EST
- Manuscript Accepted: 22 OCT 2012
- Manuscript Revised: 11 OCT 2012
- Manuscript Received: 15 AUG 2012
- 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
- asthma genetics;
- copy number variant;
- structural variant
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).
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.
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.
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.