Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

Insights into type-I edge localized modes and edge localized mode control from JOREK non-linear magneto-hydrodynamic simulations

\u3cp\u3eEdge localized modes (ELMs) are repetitive instabilities driven by the large pressure gradients and current densities in the edge of H-mode plasmas. Type-I ELMs lead to a fast collapse of the H-mode pedestal within several hundred microseconds to a few milliseconds. Localized transient heat fluxes to divertor targets are expected to exceed tolerable limits for ITER, requiring advanced insights into ELM physics and applicable mitigation methods. This paper describes how non-linear magneto-hydrodynamic (MHD) simulations can contribute to this effort. The JOREK code is introduced, which allows the study of large-scale plasma instabilities in tokamak X-point plasmas covering the main plasma, the scrape-off layer, and the divertor region with its finite element grid. We review key physics relevant for type-I ELMs and show to what extent JOREK simulations agree with experiments and help reveal the underlying mechanisms. Simulations and experimental findings are compared in many respects for type-I ELMs in ASDEX Upgrade. The role of plasma flows and non-linear mode coupling for the spatial and temporal structure of ELMs is emphasized, and the loss mechanisms are discussed. An overview of recent ELM-related research using JOREK is given, including ELM crashes, ELM-free regimes, ELM pacing by pellets and magnetic kicks, and mitigation or suppression by resonant magnetic perturbation coils (RMPs). Simulations of ELMs and ELM control methods agree in many respects with experimental observations from various tokamak experiments. On this basis, predictive simulations become more and more feasible. A brief outlook is given, showing the main priorities for further research in the field of ELM physics and further developments necessary.\u3c/p\u3