The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

The NADP(H) Redox Couple in Yeast Metabolism: Fundamental and Applied Aspects

Applied Science

In vivo 31P NMR studies on the role of the vacuole in phosphate metabolism in yeasts

31P NMR was used to study the dynamics of phosphate pools during substrate utilization by aerobic and anaerobic suspensions of the yeast Candida utilis and by aerobic suspensions of the yeast Brettanomyces intermedius. In both yeast, the cytoplasmic pH was monitored; in C. utilis also the vacuolar pH could be measured. When glucose was used as a substrate for C. utilis, the vacuolar store of inorganic phosphorus (both orthophosphate and polyphosphate) was mobilized to replenish cytoplasmic phosphate which had become very low due to the build-up of high sugar phosphate levels. The hydrolysis of polyphosphate was glucose-dependent; it did not occur with ethanol as the substrate. After glucose depletion resynthesis of polyphosphate occurred only under aerobic conditions; anaerobic C. utilis cells continued to hydrolyze vacuolar polyphosphate. This difference between the aerobic and anaerobic suspension could be related to differences in cellular ATP levels. When ethanol was employed as a substrate, both Candida utilis and Brettanomyces intermedius exhibited a substantial increase in polyphosphate levels. These observations suggested a dual role for polyphosphate in yeasts both as a phosphate and an energy store. The cytoplasmic pH in C. utilis displayed characteristic responses to metabolic changes during glucose degradation. B. intermedius experienced a strong cytoplasmic acidification upon ethanol utilization due to acetic acid formation. The mechanism of transport of Pi across the vacuolar membrane in C. utilis appeared to be different from that reported for the plasma membrane

A theoretical analysis of NADPH production and consumption in yeasts

Theoretical calculations of the NADPH requirement for yeast biomass formation reveal that this parameter is strongly dependent on the carbon and nitrogen source. The data obtained have been used to estimate the carbon flow over the NADPH-producing pathways in these organisms, namely the hexose monophosphate pathway and the NADP+-linked isocitrate dehydrogenase reaction. It was calculated that during growth of yeasts on glucose with ammonium as the nitrogen source at least 2% of the glucose metabolized has to be completely oxidized via the hexose monophosphate pathway for the purpose of NADPH synthesis. This figure increases to approximately 20% in the presence of nitrate as the nitrogen source. Not only during growth on glucose but also on other substrates such as xylose. methanol, or acetate the operation of the hexose monophosphate pathway as a source of NADPH is essential, since the N ADP+-isocitrate dehydrogenase reaction alone cannot meet the NADPH demand for anabolism. NADPH production via these pathways requires an expenditure of ATP. Therefore, the general assumption made in calculations of the ATP demand for biomass formation that generation of NADPH does not require energy is, at least in yeasts, not valid.Applied Science

An enzymic analysis of NADPH production and consumption in Candida utilis

Applied Science