A genomewide screen for chronic rhinosinusitis genes identifies a locus on chromosome 7q

Abstract

Objective/hypothesis: Chronic rhinosinusitis (CRS) is an important public health problem with substantial impact on patient quality of life and health care costs. We hypothesized that genetic variation may be one factor that affects this disease.

Study design: Identification of genetic variation underlying susceptibility to CRS using linkage analysis in a founder population.

Methods: We studied a religious isolate that practices a communal lifestyle and shares common environmental exposures. Using physical examination, medical interviews, and a review of medical records, we identified eight individuals with CRS of 291 screened. These eight individuals were related to each other in a single 60 member, nine generation pedigree. A genome-wide screen for loci influencing susceptibility to CRS using 1123 genome-wide markers was conducted.

Results: The largest linkage peak (P = .0023; 127.15 cM, equivalent to limit of detection = 2.01) was on chromosome 7q31.1-7q32.1, 7q31 (127.15 cM; 1-limit of detection support region: 115-135 cM) and included the CFTR locus. Genotyping of 38 mutations in the CFTR gene did not reveal variation accounting for this linkage signal.

Conclusions: Understanding the genes involved in CRS may lead to improvements in its diagnosis and treatment. Our results represent the first genome-wide screen for CRS and suggest that a locus on 7q31.1-7q32.1 influences disease susceptibility. This may be the CFTR gene or another nearby locus.

Figure 1

Pedigree of subjects with CRS and their ancestors.

Figure 2

P-values for Statistic E (NPL_all) on a –log₁₀ scale for each of the 22 autosomes.

Figure 3

Linkage for susceptibility to CRS for chromosome 7. Statistic A (triangles) is the number of different founder-alleles contributing alleles to the affected individuals (best used to detect linkage to a recessive trait). Statistic B (squares) is the maximum number of alleles among the affected individuals descended from any one founder-allele (best used to detect linkage to a dominant trait). Statistic E (circles) is the extent of allele sharing among all affected individuals, equivalent to the NPL_all statistic as implemented in GeneHunter (intended to detect linkage to traits in an additive model). The reduction in significance with Statistic B compared to the other statistics suggests that the 7q locus does not act in a dominant manner in the Hutterites. Position in cM according to the Decode genetic map is shown on the X-axis and –log₁₀ (P- value) of the NPL_all statistic on the Y-axis. Note: the position of the CFTR gene is 124.5 cM.