Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Wenzel SE : Asthma: defining of the persistent adult phenotypes. Lancet 2006; 368: 804–813.
Steinke JW, Rich SS, Borish L : 5. Genetics of allergic disease. J Allergy Clin Immunol 2008; 121: S384–S387.
Vercelli D : Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 2008; 8: 169–182.
Roeder K, Bacanu SA, Wasserman L, Devlin B : Using linkage genome scans to improve power of association in genome scans. Am J Hum Genet 2006; 78: 243–252.
Denham S, Koppelman GH, Blakey J et al: Meta-analysis of genome-wide linkage studies of asthma and related traits. Respir Res 2008; 9: 38.
Wise LH, Lanchbury JS, Lewis CM : Meta-analysis of genome searches. Ann Hum Genet 1999; 63: 263–272.
Zintzaras E, Ioannidis JP : Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005; 28: 123–137.
Van Eerdewegh P, Little RD, Dupuis J et al: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–430.
Balaci L, Spada MC, Olla N et al: IRAK-M is involved in the pathogenesis of early-onset persistent asthma. Am J Hum Genet 2007; 80: 1103–1114.
Kurz T, Altmueller J, Strauch K et al: A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3. Allergy 2005; 60: 192–199.
Ober C, Cox NJ, Abney M et al: Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998; 7: 1393–1398.
Wjst M, Fischer G, Immervoll T et al: A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999; 58: 1–8.
Xu J, Postma DS, Howard TD et al: Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 2000; 67: 1163–1173.
Koppelman GH, Stine OC, Xu J et al: Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol 2002; 109: 498–506.
Meyers DA, Postma DS, Stine OC et al: Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J Allergy Clin Immunol 2005; 115: 1169–1175.
Laitinen T, Daly MJ, Rioux JD et al: A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet 2001; 28: 87–91.
Bouzigon E, Dizier MH, Krahenbuhl C et al: Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families. Hum Mol Genet 2004; 13: 3103–3113.
Daniels SE, Bhattacharrya S, James A et al: A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250.
Evans DM, Zhu G, Duffy DL, Montgomery GW, Frazer IH, Martin NG : Major quantitative trait locus for eosinophil count is located on chromosome 2q. J Allergy Clin Immunol 2004; 114: 826–830.
Ferreira MA, O’Gorman L, Le Souef P et al: Robust estimation of experiment-wise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13. Am J Hum Genet 2005; 77: 1075–1085.
Pillai SG, Chiano MN, White NJ et al: A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p. Eur J Hum Genet 2006; 14: 307–316.
Hakonarson H, Bjornsdottir US, Halapi E et al: A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet 2002; 71: 483–491.
Haagerup A, Bjerke T, Schiotz PO, Binderup HG, Dahl R, Kruse TA : Asthma and atopy – a total genome scan for susceptibility genes. Allergy 2002; 57: 680–686.
Webb BT, van den Oord E, Akkari A et al: Quantitative linkage genome scan for atopy in a large collection of Caucasian families. Hum Genet 2007; 121: 83–92.
Xu J, Meyers DA, Ober C et al: Genome-wide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet 2001; 68: 1437–1446.
Colilla S, Nicolae D, Pluzhnikov A et al: Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol 2003; 111: 840–846.
Mathias RA, Freidhoff LR, Blumenthal MN et al: Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families. Genet Epidemiol 2001; 20: 340–355.
Blumenthal MN, Langefeld CD, Beaty TH et al: A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma. Hum Genet 2004; 114: 157–164.
Blumenthal MN, Ober C, Beaty TH et al: Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA). Genes Immun 2004; 5: 226–231.
Yokouchi Y, Nukaga Y, Shibasaki M et al: Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 2000; 66: 152–160.
Xu X, Fang Z, Wang B et al: A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet 2001; 69: 1271–1277.
Teerlink CC, Camp NJ, Bansal A et al: Significant evidence for linkage to chromosome 5q13 in a genome-wide scan for asthma in an extended pedigree resource. Eur J Hum Genet 2009; 17: 636–643.
Celedon JC, Soto-Quiros ME, Avila L et al: Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica. Hum Genet 2007; 120: 691–699.
Raby BA, Soto-Quiros ME, Avila L et al: Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica. Hum Mol Genet 2007; 16: 243–253.
Levinson DF, Levinson MD, Segurado R, Lewis CM : Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: methods and power analysis. Am J Hum Genet 2003; 73: 17–33.
Pardi F, Levinson DF, Lewis CM : GSMA: software implementation of the genome search meta-analysis method. Bioinformatics 2005; 21: 4430–4431.
Hermanowski J, Bouzigon E, Forabosco P, Ng MY, Fisher SA, Lewis CM : Meta-analysis of genome-wide linkage studies for multiple sclerosis, using an extended GSMA method. Eur J Hum Genet 2007; 15: 703–710.
Zintzaras E, Ioannidis JP : HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics 2005; 21: 3672–3673.
Altmuller J, Seidel C, Lee YA et al: Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families. BMC Pulm Med 2005; 5: 1.
Bouzigon E, Siroux V, Dizier MH et al: Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families. Eur Respir J 2007; 30: 253–259.
Postma DS, Meyers DA, Jongepier H, Howard TD, Koppelman GH, Bleecker ER : Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 2005; 172: 446–452.
Wilk JB, DeStefano AL, Arnett DK et al: A genome-wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Respir Crit Care Med 2003; 167: 1528–1533.
Soderhall C, Marenholz I, Kerscher T et al: Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol 2007; 5: e242.
Moffatt MF, Kabesch M, Liang L et al: Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448: 470–473.
Bouzigon E, Corda E, Aschard H et al: Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 2008; 359: 1985–1994.
A genome-wide search for asthma susceptibility loci in ethnically diverse populations: The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet 1997; 15: 389–392.
Noguchi E, Yokouchi Y, Zhang J et al: Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am J Respir Crit Care Med 2005; 172: 183–188.
Gudbjartsson DF, Bjornsdottir US, Halapi E et al: Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009; 41: 342–347.
Wjst M : Specific IgE–one gene fits all? German Asthma Genetics Group. Clin Exp Allergy 1999; 29: 5–10.
Nicolae D, Cox NJ, Lester LA et al: Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005; 76: 349–357.
Maher B : Personal genomes: the case of the missing heritability. Nature 2008; 456: 18–21.
Hardy J, Singleton A : Genome-wide association studies and human disease. N Engl J Med 2009; 360: 1759–1768.
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Bouzigon, E., Forabosco, P., Koppelman, G. et al. Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy. Eur J Hum Genet 18, 700–706 (2010). https://doi.org/10.1038/ejhg.2009.224
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2009.224
Keywords
This article is cited by
-
The state of asthma epidemiology: an overview of systematic reviews and their quality
Clinical and Translational Allergy (2017)
-
Lessons from ten years of genome‐wide association studies of asthma
Clinical & Translational Immunology (2017)
-
No Association Between −159C/T Polymorphism of the CD14 Gene and Asthma Risk: a Meta-Analysis of 36 Case-Control Studies
Inflammation (2016)
-
Association Between CD14 Polymorphism (−1145G/A) and Childhood Bronchial Asthma
Biochemical Genetics (2016)
-
Influence of MILR1 promoter polymorphism on expression levels and the phenotype of atopy
Journal of Human Genetics (2014)
