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Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

ABSTRACT: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)).By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

SUBMITTER: Ferreira MA

PROVIDER: S-EPMC4280183 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

Ferreira Manuel A R MA Matheson Melanie C MC Tang Clara S CS Granell Raquel R Ang Wei W Hui Jennie J Kiefer Amy K AK Duffy David L DL Baltic Svetlana S Danoy Patrick P Bui Minh M Price Loren L Sly Peter D PD Eriksson Nicholas N Madden Pamela A PA Abramson Michael J MJ Holt Patrick G PG Heath Andrew C AC Hunter Michael M Musk Bill B Robertson Colin F CF Le Souëf Peter P Montgomery Grant W GW Henderson A John AJ Tung Joyce Y JY Dharmage Shyamali C SC Brown Matthew A MA James Alan A Thompson Philip J PJ Pennell Craig C Martin Nicholas G NG Evans David M DM Hinds David A DA Hopper John L JL

The Journal of allergy and clinical immunology 20131231 6

<h4>Background</h4>To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.<h4>Objective</h4>We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.<h4>Methods</h4>We performed a meta-analysis of GWASs comparing p ...[more]

PMID: 24388013

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Project description:BackgroundRecent genome-wide association studies (GWAS) for asthma have been successful in identifying novel associations which have been well replicated. The aim of this study is to identify the genetic variants that influence predisposition towards asthma in an ethnic Chinese population in Singapore using a GWAS approach.MethodsA two-stage GWAS was performed in case samples with allergic asthma, and in control samples without asthma and atopy. In the discovery stage, 490 case and 490 control samples were analysed by pooled genotyping. Significant associations from the first stage were evaluated in a replication cohort of 521 case and 524 control samples in the second stage. The same 980 samples used in the discovery phase were also individually genotyped for purposes of a combined analysis. An additional 1445 non-asthmatic atopic control samples were also genotyped.Results19 promising SNPs which passed our genome-wide P value threshold of 5.52 × 10-8 were individually genotyped. In the combined analysis of 1011 case and 1014 control samples, SNP rs2941504 in PERLD1 on chromosome 17q12 was found to be significantly associated with asthma at the genotypic level (P = 1.48 × 10-6, ORAG = 0.526 (0.369-0.700), ORAA = 0.480 (0.361-0.639)) and at the allelic level (P = 9.56 × 10-6, OR = 0.745 (0.654-0.848)). These findings were found to be replicated in 3 other asthma GWAS studies, thus validating our own results. Analysis against the atopy control samples suggested that the SNP was associated with allergic asthma and not to either the asthma or allergy components. Genotyping of additional SNPs in 100 kb flanking rs2941504 further confirmed that the association was indeed to PERLD1. PERLD1 is involved in the modification of the glycosylphosphatidylinositol anchors for cell surface markers such as CD48 and CD59 which are known to play multiple roles in T-cell activation and proliferation.ConclusionsThese findings reveal the association of a PERLD1 as a novel asthma candidate gene and reinforce the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma.

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Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

Publications

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

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