In families of schoolchildren with asthma in Costa Rica, we found significant genetic contributions (heritability) to inter‐individual variation in measures of pulmonary function and BDR. The heritability estimates of FEV1
were similar in magnitude to previous studies,24
but the heritabilities of FEV1
/FVC and BDR were lower than have been reported.7
Because of low heritability, our study had limited statistical power to detect linkage to BDR. However, we had adequate statistical power to detect and found genome‐wide suggestive evidence of linkage23
to post‐bronchodilator FEV1
, on chromosome 7q34–35, which was improved after inclusion of additional STR markers.
Although no significant or suggestive evidence of linkage was found in the other genome‐wide linkage analyses in all subjects, we uncovered potential regions of interest, including chromosome 9p for BDR and chromosome 2q for FEV1/FVC. Despite a small number of smokers and correspondingly limited power, the evidence for linkage for FEV1/FVC (post‐bronchodilator) on chromosome 5p approached genome‐wide significance.
Several authors have reported genome‐wide linkage analyses for spirometric measures of pulmonary function in families ascertained through probands with asthma; however, the present study is the only genome‐wide linkage analysis of FEV1
/FVC in a Hispanic population. In a study of 2551 members of 533 families in China, Xu et al1
found the strongest evidence for linkage to FEV1
on chromosomes 10p and 22q. In 591 individuals in 202 Australian families, Ferreira et al2
showed suggestive evidence of linkage to FEV1
on chromosomes 5q, 8p, 12q, 17q and 20q and to FEV1
/FVC on chromosomes 4q, 9q and 12q. Postma et al3
showed different regions of linkage to FEV1
in genome‐wide analyses of all subjects, smokers and non‐smokers among 1183 members of 200 Dutch families. They reported genome‐wide significant evidence of linkage to FEV1
/FVC (both pre‐bronchodilator and post‐bronchodilator) on chromosome 2q.
There have been no previous reports of suggestive or significant evidence of linkage to FEV1
on chromosome 7q. However, the genome‐wide linkage analyses of pulmonary function described above were completed in populations of European and Asian descent. A unique aspect of our study is that we were able to recruit large extended pedigrees of children with asthma because of detailed genealogical records and low migration out of the relatively genetically isolated population of the Central Valley of Costa Rica. Our statistical power to detect linkage to lung function measures may have been increased by inclusion of extended pedigrees (which offer more power for linkage analysis of quantitative traits than sib‐pair studies with the same sample size)25
and by founder effects leading to relatively few susceptibility genes for asthma‐related traits in Costa Rica. On the other hand, genetic heterogeneity in determinants of lung function among the Spanish and Amerindian founders of the population of the Central Valley may have hindered our statistical power. Although the characteristics of the Costa Rican population may limit the generalisability of our results, it should be noted that the G protein coupled receptor‐154 (GPR154
) was first identified as a potential asthma‐susceptibility gene in a genetically isolated population in Finland26
and then shown to be relevant in other European nations.27,28
Thus, some of our results may be relevant across ethnic groups and others may be more relevant to Costa Ricans and other Hispanic groups of predominant Spanish and Amerindian ancestry.
Genome‐wide linkage analyses of pulmonary function have also been performed in families from the general population24,29,30,31
and in families of probands with severe, early‐onset COPD.32
Several of the regions of interest (LOD
1.5) in our study are similar to the findings in those studies (table 4), suggesting that some genomic regions are likely to contain genetic variants that influence pulmonary function in normal individuals, in patients with COPD and in those with asthma. Some of these regions may be relevant across different ethnic groups as well. In our analysis, the highest LOD score for FEV1
/FVC was found on chromosome 2q. This region overlaps the linkage peaks for FEV1
/FVC in families from the general population in Utah31
and in families from the Boston Early‐Onset COPD Study.32
/FVC linkage found in Dutch asthma families is also located on chromosome 2q, but closer to the centromere.3
Table 4Overlapping regions of linkage for pulmonary function phenotypes
The highest LOD score in any of the genome scans was found for FEV1
/FVC (post‐bronchodilator) on chromosome 5p13 in an analysis limited to former and current smokers. Despite the limited sample size, the LOD score of 3.27 approached genome‐wide significance,23
possibly identifying a locus (or loci) for smoking‐related air flow obstruction in families with a genetic predisposition to asthma, consistent with the Dutch hypothesis, which proposes a common origin for asthma and COPD. Several cadherin genes (CDH‐6, 9 and 10) are located on chromosome 5p13. E‐cadherin (CDH1), another member of the cadherin family, is a cell adhesion molecule involved in epithelial permeability in allergic asthma.34
The importance of other cadherin genes in asthma and COPD is unknown.
Although other studies of asthma have analysed both pre‐bronchodilator and post‐bronchodilator spirometry, the only previous genome‐wide linkage analysis of BDR as a distinct phenotype is from the Boston Early‐Onset COPD Study.7
An analysis limited to chromosome 12q examined BDR in families from the Childhood Asthma Management Program Study35
; the present study is the first reported genome‐wide linkage analysis of BDR in families of subjects with asthma. Similar to the Boston Early‐Onset COPD Study, we found significant heritability of BDR, although the heritability estimates in our asthma families (h2N
range 8.0–10.5% for the three BDR measures) are lower than those found in the COPD families (h2N
range 10.1–26.3%). As in our study, no significant linkage for BDR measurements was found in the Boston Early‐Onset COPD Study, although regions on chromosomes 3q and 4q had LOD scores of
The ability to detect linkage to measures of BDR may be limited by the day‐to‐day variability in BDR that is inherent in asthma. It is not clear which definition of BDR is most useful in genetic studies, so we used three commonly accepted measures.7
The fact that many of the regions with LOD scores >1 were similar across the analyses of two or all three BDR variables implies that these three definitions are likely to reflect the same underlying phenotype. The concordance of results is not perfect, as some regions were found in only one of the analyses of the BDR variables. The heritability estimates for the BDR measures were lower than those of the spirometric traits, although all heritabilities were statistically significant. This may also reduce the ability to detect significant linkage for BDR.
Additionally, as all subjects did not have post‐bronchodilator spirometry, the power in the analyses of post‐bronchodilator traits and BDR may be reduced. However, this power reduction should be minimal, as only 16 subjects did not complete the post‐bronchodilator measurements. Most patients with asthma (especially children) will have pulmonary function test values within the normal range; our study is no exception (table 1). The limited phenotype range may also limit power in genetic studies. Despite this, we were able to find suggestive evidence for linkage to FEV1.
Post‐bronchodilator spirometry is less likely to have substantial day‐to‐day variability in asthma, as the post‐bronchodilator values generally reflect underlying lung function.7
In our analysis, the strongest linkage evidence was for post‐bronchodilator FEV1
. However, pre‐bronchodilator spirometry may be more variable within an individual subject and may be more reflective of asthma symptoms and severity. Because the analyses of pre‐bronchodilator and post‐bronchodilator spirometry may yield different information on lung development, asthma severity and asthma susceptibility, we chose to perform genome scans on both pre‐bronchodilator and post‐bronchodilator phenotypes.
Even though we did not find genome‐wide significant evidence of linkage for pulmonary function or BDR, the suggestive evidence of linkage to FEV1
on chromosome 7q warrants further investigation. Several plausible asthma candidate genes are located in this region, including the T cell receptor, β subunit (TRB@
) and endothelial nitric oxide synthase (NOS3
). Polymorphisms in NOS3
have been associated with asthma in some studies36,37
but not in others.38,39
As in any genetic analysis, our findings may be due to chance or to causal genetic variants. Although our results were adjusted for multiple testing in the setting of a genome‐wide linkage analysis of a single phenotype, we did not adjust for testing of multiple traits because of correlation among lung function phenotypes. Because current methods for association studies cannot be used in a small number of extended pedigrees, we plan to assess our findings further by testing for an association between variants in candidate genes on chromosome 7q34–35 and FEV1
in nuclear families of children with asthma in Costa Rica.