Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene x environment interaction approach

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes

Novel genes for QTc interval. How much heritability is explained, and how much is left to find?

The corrected QT (QTc) interval is a complex quantitative trait, believed to be influenced by several genetic and environmental factors. It is a strong prognostic indicator of cardiovascular mortality in patients with and without cardiac disease. More than 700 mutations have been described in 12 genes (LQT1-LQT12) involved in congenital long QT syndrome. However, the heritability (genetic contribution) of QTc interval in the general population cannot be adequately explained by these long QT syndrome genes. In order to further investigate the genetic architecture underlying QTc interval in the general population, genome-wide association studies, in which up to one million single nucleotide polymorphisms are assayed in thousands of individuals, are now being employed and have already led to the discovery of variants in seven novel loci and five loci that are known to cause congenital long or short QT syndrome. Here we show that a combined risk score using 11 of these loci explains about 10% of the heritability of QTc. Additional discovery of both common and rare variants will yield further etiological insight and accelerate clinical applications

Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene–obesity interaction

Evidence from candidate gene studies suggests that obesity may modify genetic susceptibility to type 2 diabetes and dyslipidaemia. On an aggregate level, gene-obesity interactions are expected to result in different heritability estimates at different obesity levels. However, this hypothesis has never been tested. The present study included 2,180 British female twins. BMI was used as an index of general obesity. Outcome measures were insulin sensitivity (indexed by quantitative insulin-sensitivity check index [QUICKI]) and fasting plasma lipid profile. Structural equation modelling was used to test whether BMI interacted with latent genetic and environmental effects to impact on the outcome measures. Genetic influences on triacylglycerol increased with BMI (p <0.001) whereas the unique environmental influence on QUICKI decreased with BMI (p <0.001), resulting in a higher heritability estimate for both measures at higher BMI levels. This was further illustrated by stratified analysis in twin pairs concordant for normal weight and twin pairs concordant for overweight. Heritability was 19 percentage points higher for triacylglycerol (p <0.001) and 31 percentage points higher for QUICKI (p <0.01) among twins concordant for overweight than among twins concordant for normal weight. BMI had no moderator effect on the latent genetic and environmental factors for total cholesterol and HDL-cholesterol. Our results suggest that the expression of genes influencing triacylglycerol and insulin sensitivity can vary as a function of obesity status. The substantial increases in the genetic contribution to the total variance in insulin sensitivity and triacylglycerols at higher BMIs may prove extremely valuable in the search for candidate genes

Genetics of testosterone and the aggression-hostility-anger (AHA) syndrome: a study of middle-aged male twins.

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Familial co-aggregation and shared genetics of cardiometabolic disorders and traits:data from the multi-generational Lifelines Cohort Study

BACKGROUND: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study.METHODS: We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λ R) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h 2), shared environment, and genetic correlation (r g) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age 2, and sex. RESULTS: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λ FDR of 1.23 (95% CI 1.20-1.25) for hypertension to λ FDR of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λ Spouses  &lt; λ FDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h 2 CRP: 0.26 to h 2 HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λ FDR obesity-MetS: 1.28 (95% CI 1.24-1.32) to λ FDR MetS-T2D: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from r g HDL-Triglycerides: - 0.53 to r g LDL-Apolipoprotein B: 0.94). CONCLUSIONS: There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.</p