Abstract

BACKGROUND: "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution. METHODS: Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability (<i>h²</i>) of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie-2) and VEGFR1 (sFlt-1) receptor concentrations were quantile-specific. RESULTS: Quantile-specific <i>h²</i> (±SE) increased with increasing percentiles of the age- and sex-adjusted VEGF (<i>P</i>_trend&lt;10^-16), HGF (<i>P</i>_trend=0.0004), angiopoietin-2 (<i>P</i>_trend=0.0002), sTie-2 (<i>P</i>_trend=1.2 × 10^-5), and sFlt-1 distributions (<i>P</i>_trend=0.04). CONCLUSION: Heritabilities of VEGF, HGF, angiopoitein-2, sTie-2 and sFlt-1 concentrations are quantile dependent. This may explain reported interactions of genetic loci (rs10738760, rs9472159, rs833061, rs3025039, rs2280789, rs1570360, rs2010963) with metabolic syndrome, diet, recurrent miscarriage, hepatocellular carcinoma, erysipelas, diabetic retinopathy, and bevacizumab treatment in their effect on VEGF concentrations.