TY - JOUR
T1 - Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy
AU - Bouzigon, Emmanuelle
AU - Forabosco, Paola
AU - Koppelman, Gerard H.
AU - Cookson, William O.C.M.
AU - Dizier, Marie Hélène
AU - Duffy, David L.
AU - Evans, David M.
AU - Ferreira, Manuel A.R.
AU - Kere, Juha
AU - Laitinen, Tarja
AU - Malerba, Giovanni
AU - Meyers, Deborah A.
AU - Moffatt, Miriam
AU - Martin, Nicholas G.
AU - Ng, Mandy Y.
AU - Pignatti, Pier Franco
AU - Wjst, Mathias
AU - Kauffmann, Francine
AU - Demenais, Florence
AU - Lewis, Cathryn M.
N1 - Funding Information:
The 5q23.1–q33.1 region provided genome-wide evidence of linkage to SPTQ in different analyses. This linkage was supported by three scans with LOD >1.2, the fourth one having a modest signal in that region. The 5q region was also identified by the asthma analysis, this linkage signal being mainly supported by the three smallest studies (Japanese, Australian twins and Hispanic families from the CSGA study) and by the Dutch genome scan. This region was first reported to be linked to IgE and BHR by candidate linkage studies, and then detected with asthma, suggesting that this region may harbour several genes.3 Candidate genes are present within this region, including the ADRB2 gene and the interleukin gene cluster.3 Moreover, this region includes the CYFIP2 gene found to be associated with atopic asthma by positional cloning.47
Funding Information:
We thank all patients who participated in the different studies. We also thank Professors William Cookson and Pier Franco Pignatti and the EGEA cooperative group for providing unpublished results. This study was supported by the European Commission as part of the GA2LEN project, Global Allergy and Asthma European Network (contract no. FOOD-CT-2004–506378) and GABRIEL, a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community (contract no. 01896 under the Integrated Programme LSH-2004–1.2.5–1 Postgenomic approaches to understand the molecular bias of asthma aiming at a preventive or therapeutic control). This research was funded by a grant from the UK MRC to Cathryn M Lewis (G0400960). The Finnish study was supported by the Academy of Finland and Sigrid Jusélius Foundation. The Dutch family study was supported by grants from the Netherlands Asthma Foundation (AF 95.09 and 98.48) and the US National Institute of Health.
PY - 2010/6
Y1 - 2010/6
N2 - Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (≥3024 families with ≥10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
AB - Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (≥3024 families with ≥10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
KW - Asthma
KW - Atopy
KW - Linkage scan
KW - Meta-analysis
UR - https://www.scopus.com/pages/publications/77952670887
UR - https://www.scopus.com/pages/publications/77952670887#tab=citedBy
U2 - 10.1038/ejhg.2009.224
DO - 10.1038/ejhg.2009.224
M3 - Article
C2 - 20068594
AN - SCOPUS:77952670887
SN - 1018-4813
VL - 18
SP - 700
EP - 706
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 6
ER -