Dataset Information

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.

ABSTRACT:

Background

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.

Methods

We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.

Findings

Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2.

Interpretation

The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.

Funding

National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

SUBMITTER: Ferreira MA

PROVIDER: S-EPMC3517659 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.

Ferreira Manuel A R MA Matheson Melanie C MC Duffy David L DL Marks Guy B GB Hui Jennie J Le Souëf Peter P Danoy Patrick P Baltic Svetlana S Nyholt Dale R DR Jenkins Mark M Hayden Catherine C Willemsen Gonneke G Ang Wei W Kuokkanen Mikko M Beilby John J Cheah Faang F de Geus Eco J C EJ Ramasamy Adaikalavan A Vedantam Sailaja S Salomaa Veikko V Madden Pamela A PA Heath Andrew C AC Hopper John L JL Visscher Peter M PM Musk Bill B Leeder Stephen R SR Jarvelin Marjo-Riitta MR Pennell Craig C Boomsma Dorret I DI Hirschhorn Joel N JN Walters Haydn H Martin Nicholas G NG James Alan A Jones Graham G Abramson Michael J MJ Robertson Colin F CF Dharmage Shyamali C SC Brown Matthew A MA Montgomery Grant W GW Thompson Philip J PJ

Lancet (London, England) 20110901 9795

<h4>Background</h4>We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.<h4>Methods</h4>We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples ...[more]

PMID: 21907864

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Project description:Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE.From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds ?2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions.We observed an independent replication of previously observed linkage at chromosome 20p13 (P?<?0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions.With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk.

Dataset Information

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.

Background

Methods

Findings

Interpretation

Funding

Publications

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.

Similar Datasets

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