Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

Objective: Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. Methods: We performed simulations of quantitative phenotypes analysed by standard linear regression and dichotomized case-control data sets from the extremes of the quantitative trait analysed by standard logistic regression. Results: Using linear regression, markers with an effect in the extremes of the traits were almost undetectable, whereas analysing extremes by case-control design had superior power even for much smaller sample sizes. Two real data examples are provided to support our theoretical findings and to explore our mixture and parameter assumption. Conclusions: Our findings support the idea to re-analyse the available meta-analysis data sets to detect new loci in the extremes. Moreover, our investigation offers an explanation for discrepant findings when analysing quantitative traits in the general population and in the extremes. Copyright (C) 2011 S. Karger AG, Base

Gentelligent processes in biologically inspired manufacturing

Production systems have to meet quality requirements despite increasing product individuality, varying batch sizes and a scarcity of resources. The transfer of experience-based knowledge in a flexible and self-optimizing production and process planning offers the potential to meet these challenges. Biological systems solve conceptually similar challenges pertaining to the transfer of knowledge, flexibility of individual reactions and adaptation over time. Thus, in the context of digital transformation, mechanisms derived from biology are interpreted and applied to the knowledge domain of production technology. To be able to exploit the potential of bio-inspired production systems, genetic and intelligent properties of technical components and machines were identified and brought together under the concept of “Gentelligence”. Expanding upon this concept with the new idea of process-DNA and biologically inspired optimization algorithms facilitates a more flexible, learning and self-optimizing production, which is shown in three different applications. By using the new concept of gentelligent process planning it is possible to determine machine-specific process parameters in turning processes in order to ensure appropriate roughness within the requirements. Furthermore, the combination of the concept with a material removal simulation allows the determination of the resulting process force in tool grinding for subsequent unknown workpiece geometries. As a result of using the process-DNA, a workpiece-independent knowledge transfer and thus process adaptation for shape error compensation becomes possible. Gentelligent production scheduling enables a process-parallel, holistically optimized machine allocation, and as a result, a significantly reduced lead time. © 2020 The Author

Magnetometry of the classical T Tauri star GQ Lup: non-stationary dynamos & spin evolution of young Suns

We report here results of spectropolarimetric observations of the classical T Tauri star (cTTS) GQ Lup carried out with ESPaDOnS at the Canada-France-Hawaii Telescope (CFHT) in the framework of the "Magnetic Protostars and Planets" (MaPP) programme, and obtained at 2 different epochs (2009 July & 2011 June). From these observations, we first infer that GQ Lup has a photospheric temperature of 4,300+-50\^A K and a rotation period of 8.4+-0.3 d; it implies that it is a 1.05+-0.07 Msun star viewed at an inclination of ~30deg, with an age of 2-5 Myr, a radius of 1.7+-0.2 Rsun, and has just started to develop a radiative core. Large Zeeman signatures are clearly detected at all times, both in photospheric lines & in accretion-powered emission lines, probing longitudinal fields of up to 6 kG and hence making GQ Lup the cTTS with the strongest large-scale fields known as of today. Rotational modulation of Zeeman signatures is clearly different between our 2 runs, demonstrating that large-scale fields of cTTSs are evolving with time and are likely produced by non-stationary dynamo processes. Using tomographic imaging, we reconstruct maps of the large-scale field, of the photospheric brightness & of the accretion-powered emission of GQ Lup. We find that the magnetic topology is mostly poloidal & axisymmetric; moreover, the octupolar component of the large-scale field (of strength 2.4 & 1.6 kG in 2009 & 2011) dominates the dipolar component (of strength ~1 kG) by a factor of ~2, consistent with the fact that GQ Lup is no longer fully-convective. GQ Lup also features dominantly poleward magnetospheric accretion at both epochs. The large-scale dipole of GQ Lup is however not strong enough to disrupt the surrounding accretion disc further than about half-way to the corotation radius, suggesting that GQ Lup should rapidly spin up like other similar partly-convective cTTSs (abridged).Comment: MNRAS, in press (17 pages, 10 figures, 1 table

Non-replication of an association of CTNNBL1 polymorphisms and obesity in a population of Central European ancestry

<p>Abstract</p> <p>Background</p> <p>A recent genome-wide association (GWA) study of U.S. Caucasians suggested that eight single nucleotide polymorphisms (SNPs) in <it>CTNNBL1 </it>are associated with obesity and increased fat mass. We analysed the respective SNPs in data from our previously published GWA for early onset obesity (case-control design), in GWA data from a population-based cohort of adults, and in an independent family-based obesity study. We investigated whether variants in <it>CTNNBL1 </it>(including rs6013029) and in three other genes (<it>SH3PXD2B</it>, <it>SLIT3 </it>and <it>FLJ42133</it>,) were associated with obesity.</p> <p>Methods</p> <p>The GWA studies were carried out using Affymetrix^®SNP Chips with approximately 500,000 markers each. In the families, SNP rs6013029 was genotyped using the TaqMan^®allelic discrimination assay. The German case-control GWA included 487 extremely obese children and adolescents and 442 healthy lean individuals. The adult GWA included 1,644 individuals from a German population-based study (KORA). The 775 independent German families consisted of extremely obese children and adolescents and their parents.</p> <p>Results</p> <p>We found no evidence for an association of the reported variants in <it>CTNNBL1 </it>with early onset obesity or increased BMI. Further, in our family-based study we found no evidence for over-transmission of the rs6013029 risk-allele T to obese children. Additionally, we found no evidence for an association of <it>SH3PXD2B</it>, <it>SLIT3 and FLJ42133 </it>variants in our two GWA samples.</p> <p>Conclusion</p> <p>We detected no confirmation of the recent association of variants in <it>CTNNBL1 </it>with obesity in a population of Central European ancestry.</p

Synchronous and proportional deglacial changes in Atlantic meridional overturning and northeast Brazilian precipitation

Changes in heat transport associated with fluctuations in the strength of the Atlantic meridional overturning circulation (AMOC) are widely considered to affect the position of the Intertropical Convergence Zone (ITCZ), but the temporal immediacy of this teleconnection has to date not been resolved. Based on a high-resolution marine sediment sequence over the last deglaciation, we provide evidence for a synchronous and near-linear link between changes in the Atlantic interhemispheric sea surface temperature difference and continental precipitation over northeast Brazil. The tight coupling between AMOC strength, sea surface temperature difference, and precipitation changes over northeast Brazil unambiguously points to a rapid and proportional adjustment of the ITCZ location to past changes in the Atlantic meridional heat transport

Fat Mass and Obesity-Associated Gene (FTO) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-infinity; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-infinity; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN. Copyright (C) 2012 S. Karger GmbH, Freibur

Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity

There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes

The Disk Population of the Taurus Star-Forming Region

We have analyzed nearly all images of the Taurus star-forming region at 3.6-24um that were obtained during the cryogenic mission of the Spitzer Space Telescope (46 deg^2) and have measured photometry for all known members of the region that are within these data, corresponding to 348 sources. We have classified the members of Taurus according to whether they show evidence of disks and envelopes (classes I, II, and III). The disk fraction in Taurus is 75% for solar-mass stars and declines to 45% for low-mass stars and brown dwarfs (0.01-0.3 M_sun). This dependence on stellar mass is similar to that measured for Cha I, although the disk fraction in Taurus is slightly higher overall, probably because of its younger age (1 vs. 2-3 Myr). In comparison, the disk fraction for solar-mass stars is much lower (20%) in IC 348 and Sigma Ori, which are denser than Taurus and Cha I and are roughly coeval with the latter. These data indicate that disk lifetimes for solar-mass stars are longer in regions that have lower stellar densities. Through an analysis of multiple epochs of photometry that are available for ~200 Taurus members, we find that stars with disks exhibit significantly greater mid-IR variability than diskless stars. Finally, we have used our data in Taurus to refine the criteria for primordial, evolved, and transitional disks. The number ratio of evolved and transitional disks to primordial disks in Taurus is 15/98 for K5-M5, indicating a timescale of 0.15 x tau(primordial)=0.45 Myr for the clearing of the inner regions of optically thick disks. After applying the same criteria to older clusters (2-10 Myr), we find that the proportions of evolved and transitional disks in those populations are consistent with the measurements in Taurus when their star formation histories are properly taken into account. ERRATUM: In Table 7, we inadvertently omitted the spectral type bins in which class II sources were placed in Table 8 based on their bolometric luminosities (applies only to stars that lack spectroscopic classifications). The bins were K6-M3.5 for FT Tau, DK Tau B, and IRAS 04370+2559, M3.5-M6 for IRAS 04200+2759, IT Tau B, and ITG 1, and M6-M8 for IRAS 04325+2402 C. In addition, the values of K_s-[3.6] in Table 13 and Figure 26 for spectral types of M4-M9 are incorrect. We present corrected versions of Table 13 and Figure 26.Comment: revised version with Erratum (in press

Einfluss von Impfungen und Kontaktreduktionen auf die dritte Welle der SARS-CoV-2-Pandemie und perspektivische Rückkehr zu prä-pandemischem Kontaktverhalten

Das im Epidemiologischen Bulletin 13/2021 vorgestellte mathematische Modell schätzt die voraussichtlichen Effekte der COVID-19-Impfung in der Bevölkerung in Deutschland und vergleicht mögliche Strategien zur Priorisierung einzelner Bevölkerungsgruppen bei Knappheit der verfügbaren Impfstoffdosen. Das Modell ermöglicht nicht nur die Abbildung des aktuellen Infektionsgeschehens, sondern kann über Fragestellungen zur Impfstrategie hinaus auch Strategien zur Lockerung der bestehenden bzw. die Wiederaufnahme von Kontaktbeschränkungen analysieren. Dabei können saisonale Effekte auf die Übertragung von SARS-CoV-2 sowie der Einfluss neuer Virusvarianten berücksichtigt werden

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults