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Respir Res. 2018 Dec 12;19(1):248. doi: 10.1186/s12931-018-0953-2.

Identification of deleterious and regulatory genomic variations in known asthma loci.

Author information

1
Department of Biomedical and Molecular Sciences, Queen's University, Botterell Hall, Room 530 - 18 Stuart St, Kingston, ON, K7L3N6, Canada.
2
Department of Biomedical and Molecular Sciences, Queen's University, Botterell Hall, Room 530 - 18 Stuart St, Kingston, ON, K7L3N6, Canada. qingling.duan@queensu.ca.
3
School of Computing, Queen's University, 557 Goodwin Hall, Room 531, Kingston, ON, K7L 2N8, Canada. qingling.duan@queensu.ca.

Abstract

BACKGROUND:

Candidate gene and genome-wide association studies have identified hundreds of asthma risk loci. The majority of associated variants, however, are not known to have any biological function and are believed to represent markers rather than true causative mutations. We hypothesized that many of these associated markers are in linkage disequilibrium (LD) with the elusive causative variants.

METHODS:

We compiled a comprehensive list of 449 asthma-associated variants previously reported in candidate gene and genome-wide association studies. Next, we identified all sequence variants located within the 305 unique genes using whole-genome sequencing data from the 1000 Genomes Project. Then, we calculated the LD between known asthma variants and the sequence variants within each gene. LD variants identified were then annotated to determine those that are potentially deleterious and/or functional (i.e. coding or regulatory effects on the encoded transcript or protein).

RESULTS:

We identified 10,130 variants in LD (r2 > 0.6) with known asthma variants. Annotations of these LD variants revealed that several have potentially deleterious effects including frameshift, alternate splice site, stop-lost, and missense. Moreover, 24 of the LD variants have been reported to regulate gene expression as expression quantitative trait loci (eQTLs).

CONCLUSIONS:

This study is proof of concept that many of the genetic loci previously associated with complex diseases such as asthma are not causative but represent markers of disease, which are in LD with the elusive causative variants. We hereby report a number of potentially deleterious and regulatory variants that are in LD with the reported asthma loci. These reported LD variants could account for the original association signals with asthma and represent the true causative mutations at these loci.

KEYWORDS:

Asthma; Causal variants; Heritability; Linkage disequilibrium; SNPs; eQTLs

PMID:
30541564
PMCID:
PMC6292105
DOI:
10.1186/s12931-018-0953-2
[Indexed for MEDLINE]
Free PMC Article

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