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.MethodsQuantile 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., h2 = 2βOP/(1+rspouse), where rspouse was the correlation between spouses).ResultsβOP ± 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.ConclusionHeritabilities of FEV1/FVC, MMEF, and FEF75% from quantile-regression of offspring-parent and sibling spirometric data suggest their quantile-dependent expressivity.
Highlights
Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and the FEV1/FVC ratio are the most commonly measured spirometric traits (Global initiative for Chronic Obstructive Lung Disease, 2020; Wood, Tan & Stockley, 2009)
As has been reported previously in this and other cohorts (Devor & Crawford, 1984; Coultas et al, 1991; Klimentidis et al, 2013; Redline et al, 1989; Wilk et al, 2000; Tarnoki et al, 2013; Hukkinen et al, 2011; Hallberg et al, 2010; DeMeo et al, 2004; McClearn et al, 1994; Palmer et al, 2001; Astemborski, Beaty & Cohen, 1985; Beaty et al, 1987; Lewitter et al, 1984; Cotch, Beaty & Cohen, 1990; Chen et al, 1996; Chen et al, 1997; Givelber et al, 1998; Ingebrigtsen et al, 2011; Joost et al, 2002; Tian et al, 2017; Yamada et al, 2015), these analyses showed moderate to strong heritabilities for pulmonary function
The calculations of offspring-parent and full-sib quantile regression presented here assigned equal weights to each offspring (Karlin, Cameron & Williams, 1981), but there may be additional clustering within family sets not addressed by these analyses. These analyses suggest that the heritability of FEV1/FVC ratio, Maximum mid-expiratory flow (MMEF), and FEF75% are strongly dependent upon whether the offspring or sib is high or low relative to its distribution in the population
Summary
Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and the FEV1/FVC ratio are the most commonly measured spirometric traits (Global initiative for Chronic Obstructive Lung Disease, 2020; Wood, Tan & Stockley, 2009). FVC approximates lung volume and is a strong predictor of all-cause mortality (Global initiative for Chronic Obstructive Lung Disease, 2020; Wood, Tan & Stockley, 2009). Maximum mid-expiratory flow (MMEF) and forced expiratory flows at X% of FVC (i.e., FEF25%, FEF50% and FEF75%) may assess small airway caliber especially in case of a normal FVC (Wood, Tan & Stockley, 2009), its use in diagnosing small airway disease in individual patients is discouraged (Quanjer et al, 2014). Peak expiratory flow (PEF) is the maximum speed of expiration
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