Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families

Altmüller, Janine; Seidel, Corinna; Lee, Youngae; Loesgen, Sabine; Bulle, Dieter; Friedrichs, Frank; Jellouschek, Heidemarie; Kelber, Julika; Keller, Angela; Schuster, Antje; Silbermann, Michael; Wahlen, W; Wolff, Peter Th.; Schlenvoigt, G.; Rüschendorf, Franz; Nürnberg, Peter; Wjst, Matthias

doi:10.1186/1471-2466-5-1

Cited by 39 publications

(44 citation statements)

References 29 publications

(31 reference statements)

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“…However, we failed to identify a relationship between the detected heterogeneity for chromosome 2 and variation in asthma definition. Interestingly, analysis of different bin widths delineated a chromosomal region (63-83 cM) that overlaps a locus identified for severe asthma in German families 39 and is located at 10 cM from a linkage signal detected in the French EGEA study for an asthma severity score. 40 For SPT, the strongest evidence of linkage in the analysis of all families arose in the 3p25.3-q24 region.…”

Section: Discussionmentioning

confidence: 94%

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

et al. 2010

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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 (Z3024 families with Z10 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.

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Section: Discussionmentioning

confidence: 94%

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

et al. 2010

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“…Among the 16 asthma genome scans, the 18p11 region, detected for asthma score, was reported once in Australian twins for asthma analysed as a binary trait [18]. The linkage of the asthma severity score to 2p23 was detected for eosinophils in Australian twins [18,21,22] and for severe asthma in German data [23]. It should be noted that the latter study examined dichotomous subtypes of asthma, which were defined, using broader categorisation than the present study, from the three following items: asthma attack frequency, receiving asthma treatment or not, and experience or otherwise of at least one overnight hospital stay.…”

Section: Phenotype Definition and Linkage Analysis Outcomesmentioning

confidence: 99%

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

Siroux¹,

Dizier²,

Lemainque³

et al. 2007

European Respiratory Journal

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There is ongoing debate as to how asthma should be defined in order to forward understanding of the underlying mechanisms. The aim of the present study was to build quantitative scores of asthma and asthma severity and to assess whether refinement of disease phenotypes can facilitate the identification of chromosomal regions harbouring susceptibility genes.A genome-wide linkage scan was conducted in 110 families with at least two asthmatic siblings (n5508) from the French Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). The phenotypes studied were an asthma severity score (assessed among asthmatics by combining clinical data and treatment), forced expiratory volume in one second (FEV1) and an asthma score (including both asthmatics and nonasthmatics and representing the whole disease spectrum).This analysis showed genome-wide suggestive evidence of linkage of the asthma score to 18p11, a novel region undetected in a previous screen of dichotomous asthma. There was potential linkage of 2p23 to asthma severity score and of three regions (1p36, 2q36 and 6q14) to FEV1. Moreover, FEV1 appeared to have no genetic determinant in common with asthma severity and asthma scores.Asthma and asthma severity quantitative scores revealed new regions of linkage and thus provide support for considering these phenotypes in future genetic studies.

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“…Informed consent was obtained locally from all participants and all studies were approved by the local ethics committees. The individual sample sets have been described in detail elsewhere [13][14][15][16][17][18][19][20][21][22][23][24] (see also brief cohort descriptions in Supplementary text).…”

Section: Study Samplesmentioning

confidence: 99%

A sequence variant on 17q21 is associated with age at onset and severity of asthma

et al. 2010

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A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N¼4917 cases N¼34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR¼1.51, P¼6.89 . 10 À9 ) and adolescence (age: 14-17 years OR¼1.71, P¼5.47 . 10 À9 ). A weaker association was observed for onset between 6 and 13 years of age (OR¼1.17, P¼0.035), but none for adult-onset asthma (OR¼1.07, P¼0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P¼0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n¼743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

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Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families

Abstract: Background: Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication.

Cited by 39 publications

References 29 publications

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

A sequence variant on 17q21 is associated with age at onset and severity of asthma

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