A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population

Abstract

The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment. The pedigrees in our study (n=86) originate in eastern central Finland (Kainuu province). According to census records, this region had only 200 households (2,000 inhabitants) in the mid sixteenth to mid seventeenth centuries. The current population of 100,000 represents the expansion of these founders within the past 400 years. Because this population is relatively homogeneous, we hypothesized that the molecular genetic mechanisms underlying asthma might also have reduced heterogeneity and therefore be easier to dissect than in mixed populations. A recent twin family study supported a strong genetic component for asthma in Finland. We carried out a genome-wide scan for susceptibility loci in asthma in the Kainuu subpopulation. We identified two regions of suggestive linkage and studied them further with higher-density mapping. We obtained evidence for linkage in a 20-cM region of chromosome 7p14-p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes. The strongest linkage was seen for high serum IgE (non-parametric linkage (NPL) score 3.9, P=0.0001), exceeding the threshold for genome-wide significance based on simulations. We also observed linkage between this locus and asthma or atopy in two independent data sets.

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

“…We used 42 microsatellites together with 12 SNPs for chromosome 5, and 11 microsatellites with 9 SNPs for chromosome 16 placed evenly across the chromosome [18,21]. Neither of the candidate regions showed any evidence of linkage, confirming our previous observations [18].…”

“…Both chromosomes 5 and 16 were analyzed for linkage using the computer package GENEHUNTER 2.0 [26]. The SNP genotypes were combined with 42 polymorphic microsatellites for chromosome 5 and with 11 microsatellites for chromosome 16 from our genome scan [21].…”

Physical map of an asthma susceptibility locus in 7p15-p14 and an association study of TCRG

“…Among Finnish asthma families, this locus was the only locus that reached genome wide significance level. 1 The finding was further confirmed among French-Canadian families and in another independent data set from Finland. 1 Daniels et al 2 have reported six regions of possible linkage, including 7p14-p15, and established by simulations that at least some of them are likely to be true positives.…”

An association between asthma and TNF-308G/A polymorphism: meta-analysis

“…Asthma is believed to be a complex disorder involving genetic and environmental factors, and several asthma susceptibility loci have been identified through genome-wide screening (Daniels et al 1996;Ober et al 1998;Wjst et al 1999;Dizier et al 2000;Yokouchi et al 2000;Laitinen et al 2001). Tumor necrosis factor (TNF) gene is located on chromosome 6p21 within the major histocompatibility complex class III region (Carroll et al 1987), which has been linked to asthma by several genome-wide linkage studies (Daniels et al 1996;Wjst et al 1999;Yokouchi et al 2000;Nicolae et al 2005).…”