A major susceptibility gene for asthma maps to chromosome 14q24

Abstract

Asthma is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Numerous loci and candidate genes have been reported to show linkage and association to asthma and atopy. Although some studies reporting these observations are compelling, no gene has been mapped that confers a sufficiently high risk of asthma to meet the stringent criteria for genomewide significance. Using 175 extended Icelandic families that included 596 patients with asthma, we performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the Department of Allergy/Pulmonary Medicine of the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. We detected linkage of asthma to chromosome 14q24, with an allele-sharing LOD score of 2.66. After we increased the marker density within the locus to an average of one microsatellite every 0.2 cM, the LOD score rose to 4.00. We designate this locus "asthma locus one" (AS1). Taken together, these results provide evidence of a novel susceptibility gene for asthma on chromosome 14q24.

Figure 1

Examples of asthma pedigrees used in the linkage analysis. Unaffected siblings of patients are not shown, and sex indicators have been shuffled for some individuals in the top two generations, to protect privacy. The darkened squares and circles represent affected men and women, respectively. The slashed symbols represent deceased individuals.

Figure 2

Genealogy-based genomewide linkage scan of all 596 affected family members, using 976 microsatellite markers. The multipoint LOD score is shown on the vertical axis, and the distance (in cM) from the p terminus of the chromosome is on the horizontal axis.

Figure 3

Multipoint allele-sharing LOD score of chromosome 14. A framework genome scan is indicated by a dotted line. A fine-mapping LOD score of 4.00 was detected within the peak region after 34 microsatellite markers were added to obtain a marker density of ⩽0.2 cM, using deCODE's high-density genetic map to determine genetic distances. The multipoint LOD score is shown on the vertical axis, and distance (in cM) from the p terminus of the chromosome is shown on the horizontal axis.