Supplementary Material for: Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

<b><i>Background:</i></b> “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. <b><i>Methods:</i></b> Quantile-specific offspring-parent regression slopes (β_OP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. <b><i>Results:</i></b> Quantile-specific heritability (<i>h</i>²), estimated by 2β_OP/(1 + <i>r</i>_spouse), increased 0.0045 ± 0.0007 (<i>p</i> = 8.8 × 10⁻¹⁴) for each 1% increment in the fasting glucose distribution, that is, <i>h</i>² ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (<i>p</i> = 1.2 × 10⁻⁶), homeostatic model assessment of insulin resistance (HOMA-IR, <i>p</i> = 5.3 × 10⁻⁵), insulin/glucose ratio (<i>p</i> = 3.9 × 10⁻⁵), proinsulin (<i>p</i> = 1.4 × 10⁻⁶), proinsulin/insulin ratio (<i>p</i> = 2.7 × 10⁻⁵), and glucose concentrations during a glucose tolerance test (<i>p</i> = 0.001), and their logarithmically transformed values. <b><i>Discussion/Conclusion:</i></b> These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between <i>ACE, ADRB3</i>, <i>PPAR-γ2</i>, and <i>TNF-α</i> polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (<i>APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2</i>), gene-exercise (<i>INS</i>), gene-diet (<i>ACSL1</i>, <i>ELOVL6</i>, <i>IRS-1</i>, <i>PLIN</i>, <i>S100A9</i>), and gene-socioeconomic interactions.