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. 2020 May 15:8:e9145.
doi: 10.7717/peerj.9145. eCollection 2020.

Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution

Paul T Williams  1
Affiliations

Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution

Paul T Williams. PeerJ. .

Abstract

Background: "Quantile-dependent expressivity" refers to a genetic effect that is dependent upon whether the phenotype (e.g., spirometric data) is high or low relative to its population distribution. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the FEV1/FVC ratio are moderately heritable spirometric traits. The aim of the analyses is to test whether their heritability (h2 ) is constant over all quantiles of their distribution.

Methods: Quantile regression was applied to the mean age, sex, height and smoking-adjusted spirometric data over multiple visits in 9,993 offspring-parent pairs and 1,930 sibships from the Framingham Heart Study to obtain robust estimates of offspring-parent (βOP), offspring-midparent (βOM), and full-sib regression slopes (βFS). Nonparametric significance levels were obtained from 1,000 bootstrap samples. βOPs were used as simple indicators of quantile-specific heritability (i.e., h 2 = 2βOP/(1+rspouse), where rspouse was the correlation between spouses).

Results: βOP ± standard error (SE) decreased by 0.0009 ± 0.0003 (P = 0.003) with every one-percent increment in the population distribution of FEV1/FVC, i.e., βOP ± SE were: 0.182 ± 0.031, 0.152 ± 0.015; 0.136 ± 0.011; 0.121 ± 0.013; and 0.099 ± 0.013 at the 10th, 25th, 50th, 75th, and 90th percentiles of the FEV1/FVC distribution, respectively. These correspond to h2 ± SEs of 0.350 ± 0.060 at the 10th, 0.292 ± 0.029 at the 25th, 0.262 ± 0.020 at the 50th, 0.234 ± 0.025 at the 75th, and 0.191 ± 0.025 at the 90th percentiles of the FEV1/FVC ratio. Maximum mid-expiratory flow (MMEF) h2 ± SEs increased 0.0025 ± 0.0007 (P = 0.0004) with every one-percent increment in its distribution, i.e.: 0.467 ± 0.046, 0.467 ± 0.033, 0.554 ± 0.038, 0.615 ± 0.042, and 0.675 ± 0.060 at the 10th, 25th, 50th, 75th, and 90th percentiles of its distribution. This was due to forced expiratory flow at 75% of FVC (FEF75%), whose quantile-specific h2 increased an average of 0.0042 ± 0.0008 for every one-percent increment in its distribution. It is speculated that previously reported gene-environment interactions may be partially attributable to quantile-specific h2 , i.e., greater heritability in individuals with lower FEV1/FVC due to smoking or airborne particles exposure vs. nonsmoking, unexposed individuals.

Conclusion: Heritabilities of FEV1/FVC, MMEF, and FEF75% from quantile-regression of offspring-parent and sibling spirometric data suggest their quantile-dependent expressivity.

Keywords: COPD; Forced vital capacity; Gene environment interaction; Heritability; Pollution; Pulmonary function; Quantile dependent expressivity; SERPINA1; Smoking; Spirometric data.

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Conflict of interest statement

The author declares there are no competing interests.

Figures

Figure 1
Figure 1. Offspring-parent regression slopes (βOP) for selected quantiles of the offsprings’ FEV1/FVC ratio (10th, 25th, 50th, 75th, 90th).
(A) Offspring-parent regression slopes (βOP) for selected quantiles of the offspring’s FEV1/FVC distribution (10th, 25th, 50th, 75th, 90th) for quantile regression analyses of 6,223 offspring, showing increasing regression slope with decreasing percentiles of the offspring’s distribution. (B) The slopes from A were included with those of other quantiles to create the quantile-specific heritability plot. The shaded area presents the 95% confidence intervals for the individual slopes at each quantile. Quantile-specific heritability (h2) was calculated as 2βOP∕(1 + rspouse) where rspouse = 0.04.
Figure 2
Figure 2. Full-sib regression slopes for FEV1/FVC ratio.
Full-sib regression slopes (βFS) for 5,122 sibling from 1,930 sibships showing higher full-sib regression slope for the lower percentiles of the siblings’ FEV 1/FVC distribution. The shaded area presents the 95% confidence intervals for the individual slopes at each quantile from 1,000 bootstrapped samples. The significance levels of the linear, quadratic and cubic component of the quantile-specific slope function were computed from orthogonal contrasts.
Figure 3
Figure 3. Offspring-parent and full-sib quantile regression slopes for forced vital capacity (FVC).
(A) Offspring-parent (N = 6,231 offspring) and (B) full-sib quantile regression slopes (5,122 offspring in 1,930 sibships) for FVC. The shaded area presents the 95% confidence intervals for the slopes at each quantile from 1,000 bootstrapped samples. The nonsignificant linear, quadratic and cubic component of the quantile-specific heritability (A) and slope functions (B) were computed from orthogonal contrasts. Quantile-specific heritability (h2) was calculated as 2βOP∕(1 + rspouse) where rspouse = 0.08.
Figure 4
Figure 4. Offspring-parent and full-sib quantile regression for forced expiratory volume at 1 second (FEV 1).
(A) Offspring-parent (N = 6,223 offspring) and (B) full-sib quantile regression slopes (N = 5,122 offspring in 1,930 sibships) for FEV 1. The shaded area presents the 95% confidence intervals for the slopes at each quantile from 1,000 bootstrapped samples. Significance for linear, quadratic and cubic component of the quantile-specific heritability and slope functions were computed from orthogonal contrasts. Quantile-specific heritability (h2) was calculated as 2βOP∕(1 + rspouse) where rspouse = 0.08.
Figure 5
Figure 5. Offspring-parent and full-sib quantile regression slopes for peak expiratory flow (PEF).
(A) Offspring-parent (N = 4,686 offspring) and (B) full-sib quantile regression slopes (N = 5,122 offspring in 1,930 sibships) for PEF. The shaded area presents the 95% confidence intervals for the slopes at each quantile from 1,000 bootstrapped samples. The nonsignificant linear, quadratic and cubic component of the quantile-specific heritability and slope function were computed from orthogonal contrasts. Quantile-specific heritability (h2) was calculated as 2βOP∕(1 + rspouse) where rspouse = 0.05.
Figure 6
Figure 6. Offspring-parent and full-sib quantile regression for maximum-mid expiratory flow (MMEF).
(A) Offspring-parent (N = 5,497 offspring) and (B) full-sib quantile regression slopes (N = 5,122 offspring in 1,930 sibships) for MMEF. The shaded area presents the 95% confidence intervals for the slopes at each quantile from 1,000 bootstrapped samples. The nonsignificant linear, quadratic and cubic component of the quantile-specific heritability function were computed from orthogonal contrasts. Quantile-specific heritability (h2) was calculated as 2βOP∕(1 + rspouse) where rspouse = 0.04.
Figure 7
Figure 7. Offspring-parent and full-sib quantile regression slopes for FEF25%, FEF50% and FEF75%.
(A) Offspring-parent (N = 5,497 offspring) and (B) full-sib quantile regression slopes (5,122 offspring in 1,930 sibships) for FEF25%, FEF50% and FEF75%. The shaded area presents the 95% confidence intervals for the slopes at each quantile from 1,000 bootstrapped samples. The nonsignificant linear, quadratic and cubic component of the quantile-specific heritability function were computed from orthogonal contrasts. Quantile-specific heritability is for forces expired flow at 75% (rspouse = 0.01), those for 50% (rspouse = 0.06) and 25% (rspouse = 0.07) would be slightly lower.
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