Quantile-specific heritability of high-density lipoproteins with implications for precision medicine

Abstract

BACKGROUND: We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity). OBJECTIVE: Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h 2) in a larger population (Framingham cohort). METHODS: Quantile regression was used to test whether the offspring-parent (b OP) and full-sib (b FS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2b OP /(1 1 r spouse) and [(8b FS r spouse 1 1) 0.5 21]/(2r spouse), where r spouse is the spouse correlation. RESULTS: HDL cholesterol heritability estimated from b OP increased significantly (P 5 4.2 ! 10 25) from the 10 th (h 2 6 SE: 0.44 6 0.03), 25 th (0.45 6 0.03), 50 th (0.47 6 0.03), and 75 th (0.56 6 0.04) to the 90 th percentiles (0.65 6 0.06) of the offspring's age-and sex-adjusted HDL cholesterol distribution. Heritability estimated from b FS also increased significantly with the percentiles of the offspring's HDL cholesterol (P 5 .002), apo A1 (P 5 .006), HDL2 cholesterol (P 5 .003), and HDL3 cholesterol distribution (P 5 .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects. CONCLUSION: : HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.

Quantile-dependent expressivity of plasma adiponectin concentrations may explain its sex-specific heritability, gene-environment interactions, and genotype-specific response to postprandial lipemia

“…1 suggests that the transformation accentuates the genetic effect at low concentrations (where the genetic effects are weakest) and diminishes the genetic effect at higher values concentrations (where the genetic effects are strongest). Our previous analyses (Williams, 2012;Williams, 2020c;Williams, 2020e;Williams, 2020a;Williams, 2020b) suggest this concern is also apropos to lipoproteins and adiposity GWAS.…”

“…The methods have been described previously (Williams, 2020c;Williams, 2020e;Williams, 2020a;Williams, 2020g), but are repeated here for completeness. The data were obtained from the National Institutes of Health FRAMCOHORT, GEN3, FRAMOFFSPRING Research Materials obtained from the National Heart Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center.…”

“…This is in contrast to the traditional estimate of a genetic effect size that is assumed to be constant across all population percentiles. Quantile-dependent expressivity has been demonstrated for adiposity ( Williams, 2012 ; Williams, 2020c ), lipoproteins ( Williams, 2012 ; Williams, 2020e ; Williams, 2020a ), pulmonary function ( Williams, 2020g ), coffee intake ( Williams, 2020d ), and alcohol intake ( Williams, 2020f ). Moreover, the genetic effect sizes of single nucleotide polymorphisms (SNPs) affecting triglycerides have been shown to increase and decrease within individuals in accordance with increasing and decreasing postprandial triglyceride concentrations, consistent with quantile-dependent expressivity ( Williams, 2020b ).…”

“…An important consequence of quantile-dependent expressivity is that the selection of subjects for characteristics that distinguish high vs. low phenotypes can yield different genetic effects ( Williams, 2012 ; Williams, 2020e ). Adiponectin concentrations are greater in women than men ( Liu et al, 2008 ; Hicks et al, 2007 ; Comuzzie et al, 2001 ; Vaughan et al, 2015 ; Chuang et al, 2004 ; Dosaev, Prakash & Livshits, 2014 ; Henneman et al, 2010 ; Guo et al, 2006 ; Ling, Waterworth et al, 2009 ; Vasseur et al, 2002 ; Cesari et al, 2007 ; Berra et al, 2006 ), increase with rosiglitazone treatment ( Kang et al, 2005 ), increase during postprandial lipemia ( Musso et al, 2008 ), and decrease with adiposity ( De Luis et al, 2020 ; De Luis et al, 2018 ; De Luis et al, 2019 ; Corbi et al, 2019 ; Divella et al, 2017 ; Garcia-Garcia et al, 2014 ; Berthier et al, 2005 ; Aller et al, 2019 ).…”

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

“…The methods have been described previously [25][26][27][28][29][30][31][32][33] , but are repeated here for completeness. The data were obtained from the National Institutes of Health FRAMCOHORT, GEN3, FRAMOFFSPRING Research Materials obtained from the National Heart Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center.…”