Tackling Missing Heritability by Use of an Optimum Curve: A Systematic Review and Meta-Analysis.

Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short/long (S/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations.

GLOBOX: A spatially differentiated global fate, intake and effect model for toxicity assessment in LCA.

GLOBOX is a model for the calculation of spatially differentiated LCA toxicity characterisation factors on a global scale. It can also be used for human and environmental risk assessment. The GLOBOX model contains equations for the calculation of fate, intake and effect factors, and equations for the calculation of LCA characterisation factors for human toxicity and ecotoxicity. The model is differentiated on the level of 239 countries/territories and 50 seas/oceans. Each region has its own set of homogeneous compartments, and the regions are interconnected by atmospheric and aquatic flows. Multimedia transport and degradation calculations are largely based on the EUSES 2.0 multimedia model, and are supplemented by specific equations to account for the advective air and water transport between different countries and/or seas. Metal-specific equations are added to account for speciation in fresh and marine surface water. Distribution parameters for multimedia transport equations are differentiated per country or sea with respect to geographic features, hydrology, and climate. The model has been tested with nitrobenzene as a test chemical, for emissions to all countries in the world. Spatially differentiated characterisation factors turn out to show wide ranges of variation between countries, especially for releases to inland water and soil compartments. Geographic position, distribution of lakes and rivers and variations in environmental temperature and rain rate are decisive parameters for a number of different characterisation factors. Population density and dietary intake play central roles in the variation of characterisation factors for human toxicity. Among the countries that show substantial deviations from average values of the characterisation factors are not only small and remote islands, but also countries with a significant economic production rate, as indicated by their GDPs. It is concluded that spatial differentiation between countries is an important step forward with respect to the improvement of LCA toxicity characterisation factors.