Separating within and between effects in family studies: an application to the study of blood pressure in children.

In epidemiology the analyses of family or twin studies do not always fully exploit the data, as information on differences between siblings is often used while between-families effect are not considered. We show how cross-sectional time-series linear regression analysis can be easily implemented to estimate within- and between-families effects simultaneously and how these effects can then be compared using the Hausman test. We illustrate this approach with data from the Uppsala family study on blood pressure in children with age ranging from 5.5 to 12.3 years for the younger and from 7.5 to 13.8 years for the older siblings. Comparing the effect of differences in birth weight on blood pressure within-family (in full siblings) and between-families (in unrelated children) allows us to study the contributions of fixed and pregnancy-specific maternal effects on birth weight and consequently on blood pressure. Our data showed a 0.88 mmHg decrease (95 per cent confidence interval: -1.7 to -0.03 mmHg) in systolic blood pressure for one standard deviation increase in birth weight between siblings within a family and 0.88 mmHg (95 per cent confidence interval: -1.6 to -0.2 mmHg) decrease in systolic blood pressure for one standard deviation increase in birth weight between unrelated children. These estimates were controlled for sex, age, pubertal stage, body size and pulse rate of the children at examination and for maternal body size and systolic blood pressure. The within- and between-families effects were not significantly different, p = 0.19, suggesting that fixed and pregnancy-specific factors have similar effects on childhood systolic blood pressure

Reduced CD300LG mRNA tissue expression, increased intramyocellular lipid content and impaired glucose metabolism in healthy male carriers of Arg82Cys in CD300LG:a novel genometabolic cross-link between CD300LG and common metabolic phenotypes

BACKGROUND: CD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability to recognize and interact with extracellular lipids. We tested whether this specific polymorphism results in abnormal lipid accumulation in skeletal muscle and liver and other indices of metabolic dysfunction. METHODS: 40 healthy men with a mean age of 55 years were characterized metabolically including assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) and intramyocellular lipid content (IMCL) by MR spectroscopy, and β-cell function by an intravenous glucose tolerance test. Changes in insulin signaling and CD300LG mRNA expression were determined by western blotting and quantitative PCR in muscle and adipose tissue. RESULTS: Compared with the 20 controls (CC carriers), the 20 CT carriers (polymorphism carriers) had higher IMCL (p=0.045), a reduced fasting forearm glucose uptake (p=0.011), a trend toward lower M-values during the clamp; 6.0 mg/kg/min vs 7.1 (p=0.10), and higher IHLC (p=0.10). CT carriers had lower CD300LG mRNA expression and CD300LG expression in muscle correlated with IMCL (β=−0.35, p=0.046), forearm glucose uptake (β=0.37, p=0.03), and tended to correlate with the M-value (β=0.33, p=0.06), independently of CD300LG genotype. β-cell function was unaffected. CONCLUSIONS: The CD300LG polymorphism was associated with decreased CD300LG mRNA expression in muscle and adipose tissue, increased IMCL, and abnormalities of glucose metabolism. CD300LG mRNA levels correlated with IMCL and forearm glucose uptake. These findings link a specific CD300LG polymorphism with features of the metabolic syndrome suggesting a role for CD300LG in the regulation of common metabolic traits. TRIAL REGISTRATION NUMBER: NCT01571609

The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes

A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained

Studies of association of AGPAT6 variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes

BACKGROUND: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population. METHODS: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case–control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study. RESULTS: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case–control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity. CONCLUSIONS: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Genetic contribution to the etiology of Achilles tendon rupture. A Danish nationwide register study of twins

Background: It is unknown if genetics contribute to the etiology of acute Achilles tendon rupture (ATR). The aims of the present study were, 1) To calculate the concordance rate for monozygotic (MZ) twins and same-sex dizygotic (SSDZ) twins and 2) to estimate the heritability of ATR. Methods: The study was performed as a registry study using the Danish Twin Registry and the Danish National Patient Registry. Results: The study sample consisted of 85,534 twins born from 1895 to 1995. Of these, 572 (0.67%) were registered with ATR in the period from 1994 to 2014. The concordance rate was 8.1% (95% CI 1.4–14.7%) for MZ twins and 4.3% (95% CI 0.7–7.9%) for SSDZ twins. The heritability of ATR was 47% (95% CI 31–62%). Conclusion: This study found that genetics contribute substantially to the etiology of ATR with an estimated heritability of the liability to ATR of approximately 50%. The finding generates the hypothesis that genetics play a role in the pathological changes that occur in the Achilles tendon before a rupture. The risk of ATR for a twin within a 20 year period, if the co-twin has had an ATR, was 8% for MZ twins and 4% for SSDZ twins.</p

Fire at high latitudes: Data-model comparisons and their consequences

Fire is an endemic process at high latitudes, connected to a range of other land surface properties, such as land cover, biomass, and permafrost, and intimately linked to the carbon balance of the high-latitude land surface. Much of our current understanding of these links and their climate consequences is through land surface models, so it is important to ensure that for their credibility, these models should be consistent with available data. Over the vast panboreal region, a key source of information on fire is satellite data. Comparisons between satellite-based burned area data from the Global Fire Emissions Database and three dynamic vegetation models (LPJ-WM, CLM4CN, and SDGVM) indicate that all models fail to represent the observed spatial and temporal properties of the fire regime. Although the three dynamic vegetation models give comparable values of the boreal net biome production (NBP), fire emissions are found to differ by a factor 4 between the models, because of widely different estimates of burned area and because of different parameterizations of the fuel load and combustion process. Including a more realistic representation of the fire regime in the models shows that for northern high latitudes, (i) severe fire years do not coincide with source years or vice versa, (ii) the interannual variability of fire emissions does not significantly affect the interannual variability of NBP, and (iii) overall biomass values alter only slightly, but the spatial distribution of biomass exhibits changes. We also demonstrate that it is crucial to alter the current representations of fire occurrence and severity in land surface models if the links between permafrost and fire are to be captured, in particular, the dynamics of permafrost properties, such as active layer depth. This is especially important if models are to be used to predict the effects of a changing climate, because of the consequences of permafrost changes for greenhouse gas emissions, hydrology, and land cover

Stochastic semiclassical gravity

In the first part of this paper, we show that the semiclassical Einstein-Langevin equation, introduced in the framework of a stochastic generalization of semiclassical gravity to describe the back reaction of matter stress-energy fluctuations, can be formally derived from a functional method based on the influence functional of Feynman and Vernon. In the second part, we derive a number of results for background solutions of semiclassical gravity consisting of stationary and conformally stationary spacetimes and scalar fields in thermal equilibrium states. For these cases, fluctuation-dissipation relations are derived. We also show that particle creation is related to the vacuum stress-energy fluctuations and that it is enhanced by the presence of stochastic metric fluctuations.Comment: 26 pages, RevTeX, no figure

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF &lt;5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants