Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers

Abstract

Rationale: Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have shown that spirometric phenotypes are heritable.

Objectives: To assess the heritability and coheritability of four major COPD-related phenotypes (measurements of FEV1, FEV1/FVC, percent emphysema, and percent gas trapping), and COPD affection status in smokers of non-Hispanic white and African American descent using a population design.

Methods: Single-nucleotide polymorphisms from genome-wide association studies chips were used to calculate the relatedness of pairs of individuals and a mixed model was adopted to estimate genetic variance and covariance.

Measurements and main results: In the non-Hispanic whites, estimated heritabilities of FEV1 and FEV1/FVC were both about 37%, consistent with estimates in the literature from family-based studies. For chest computed tomography scan phenotypes, estimated heritabilities were both close to 25%. Heritability of COPD affection status was estimated as 37.7% in both populations.

Conclusions: This study suggests that a large portion of the genetic risk of COPD is yet to be discovered and gives rationale for additional genetic studies of COPD. The estimates of coheritability (genetic covariance) for pairs of the phenotypes suggest considerable overlap of causal genetic loci.

Figure 1.

Chromosomal partition of phenotypes FEV₁/FVC in non-Hispanic white sample. Error bars are the standard error for each estimate.

Figure 2.

Chromosomal partition of percent of emphysema in non-Hispanic white sample. Error bars are the standard error for each estimate.

Figure 3.

Variance caused by cryptic relatedness and population stratification. Shown is the difference between the estimates of variance explained by each chromosome by the separate (Sep) and joint analyses for FEV₁/FVC. Numbers next to each dot are the chromosome numbers. Straight line is the regression line (difference between analysis separately and jointly regressed on chromosomal length.)

Figure 4.

Variance caused by cryptic relatedness and population stratification. Shown is the difference between the estimates of variance explained by each chromosome by the separate (Sep) and joint analyses for percent of emphysema. Numbers next to each dot are the chromosome numbers. Straight line is the regression line (difference between analysis separately and jointly regressed on chromosomal length.)