Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.

Figure 1

Multipoint variance-component linkage analysis of all 22 autosomes in pedigrees with early-onset COPD. Results of linkage analysis are presented for FEV₁, FEV₁/FVC, and FVC, with adjustment for relevant covariates. Genetic distance (in cM), from version 10 of the Marshfield map, is plotted against variance-component LOD score. Significant linkage was demonstrated for FEV₁/FVC, on chromosome 2 (LOD score 4.12).

Figure 2

Multipoint variance-component linkage analysis of chromosome 12, including STR markers from the initial genomewide scan, as well as 12 additional markers. Genetic distance (in cM), from version 10 of the Marshfield map, is plotted against the multipoint variance-component LOD score for FEV₁, FEV₁/FVC, and FVC. For FEV₁, a maximum LOD score of 2.43 was observed at 37 cM.