Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan

Geological history of the Winchcombe meteorite - A new cm Chrondrite fall

Introduction: The Mighei-like (CM) carbonaceous chondrites are the largest class of hydrated meteorites, representing collisionally derived fragments of water-rich asteroids [1,2]. Most (>95%) are breccias, whose clasts sample a range of aqueous alteration extents [3]. They can therefore act as “snapshots” recording the progression of fluidrock interaction on the CM parent body. Conversely, analysis of the material between clasts (termed cataclastic matrix) provides an opportunity to study the post-hydration history of the CM parent body, specifically its fragmentation and re-accretion. Here, we investigate both aspects of the CM chondrites’ geological history through study of the newly recovered fall: Winchcombe [4, 5]. Methods: Sixteen polished sections with a total area of 190 mm2 were generated for this work. They were studied under scanning electron microscopy (SEM) using backscattered electron (BSE) imaging, energy dispersive X-ray spectroscopy (EDX) and electron microprobe analysis (EMPA). These sections sample the two largest masses (the main mass [320 g] and the agricultural field stone [152 g]) recovered from the Winchcombe strewn field [4]. Results: Winchcombe is a breccia, composed of lithological clasts held within a cataclastic matrix. We identified eight distinct lithologies. Their aqueous alteration extents vary between intensely altered CM2.0 and moderately altered CM2.6 [6]. Although no lithology dominates, three rock types represent >70% of the studied area. Several lithologies contain abundant tochilinite-cronstedtite intergrowths (TCIs). Type-II forms with zoned textures are most common, typically they have Fe-rich rims (“FeO”/SiO2 wt.%: 1-5) and Mg-rich cores (“FeO”/SiO2 wt.%: < 1), however, forms with hollow cores or cores containing a mix of phyllosilicate and calcite or phyllosilciates and anhydrous silicate are also found. The cataclastic matrix represents ~15% of the studied area. It has a coarse, heterogenous texture and includes abundant subangular fragments. Fragments include the full range of CM chondrite components (e.g. Fe-sulphides, whole chondrules with or without fine-grained rims, olivine and pyroxene grains, serpentine, carbonate grains, TCI clusters, as well as coherent blocks of fine-grained matrix). The cataclastic matrix is, therefore, a complex mix of components, with both heavily altered and mildly altered phases found in close association. Another striking feature is the apparent low abundance (< 3 area%) of identifiable whole chondrules. Discussion and conclusions: Our data suggest that both anhydrous silicates and carbonates (T1a calcites) act as precursor phases for type-II TCI formation. Cross-cutting relationships allow the sequence of mineralization to be reconstructed. Initially, inward dissolution by Fe-rich and S-rich fluids forms rims composed of intermixed tochilinite and cronstedtite. In the intermediate stages of type-II TCI formation, further dissolution continues without concurrent precipitation, resulting in the formation of hollow structures. These voids were later infilled, most often by Mg-rich phyllosilicates. As alteration advanced, early-formed secondary phases became unstable and were either dissolved (e.g. T1a calcites) or chemically altered (e.g. TCI rims). The presence of numerous lithological clasts with variable aqueous alteration extents and abrupt boundaries found in close juxtaposition indicates that the cataclastic matrix formed by the deposition of fines, alongside larger fragments (the clasts), on or near the surface of the parent asteroid. Furthermore, the composition of the cataclastic matrix is consistent with formation by fragmentation and mixing of debris derived from the entire clast population. The cataclastic matrix is, therefore, interpreted as an impact-derived fallback breccia. Analysis of grain size and texture suggests that disruption of the original parent asteroid responded by intergranular fracture at grain sizes <100 μm, while larger phases, such as whole chondrules, splintered apart. Re-accretion formed a poorly lithified rubble-pile body. During atmospheric entry, the meteoroid broke apart with new fractures preferentially cutting through the weaker cataclastic matrix and thereby separating the Winchcombe meteoroid into its component- lithological clasts. Thus, the strength of the cataclastic matrix imparts a significant control on the survival of CM chondrite meteoroids. References: [1] McSween, 1979. GCA, 43:1761-1770. [2] Suttle et al. 2021. GCA, 299:219-256. [3] Bischoff, et al. 2017, 80th MetSoc. (Abstr.#6089), [4] Meteoritical Bulletin Database, Winchcombe entry (available at: https://www.lpi.usra.edu/meteor/metbull.php?code=74388). [5] Daly et al., (this meeting). [6] Rubin et al. 2007,GCA, 71:2361-2382

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

A meta-analysis of genome-wide association studies identifies multiple longevity genes

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity

De immigratievoorstellen van het regeerakkoord ontrafeld

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De immigratievoorstellen van Rutte II ontrafeld

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De immigratievoorstellen van het regeerakkoord ontrafeld II

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Clostridium perfringens type A enterotoxin forms mepacrine-sensitive pores in pure phospholipid bilayers in the absence of putative receptor proteins

AbstractClostridium perfringens enterotoxin (CPE) is an important cause of food poisoning with no significant homology to other enterotoxins and its mechanism of action remains uncertain. Although CPE has recently been shown to complex with tight junction proteins, we have previously demonstrated that CPE increases ionic permeability in single Caco-2 cells using the whole-cell patch-clamp technique, thereby excluding any paracellular permeability. In this paper we demonstrate that CPE forms pores in synthetic phospholipid membranes in the absence of receptor proteins. The properties of the pores are consistent with CPE-induced permeability changes in Caco-2 cells suggesting that CPE has innate pore-forming ability