Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolis

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris—Analysis of Four Different Ethnic Cohorts

IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Jewish identity and figures of otherness in Gertrud Kolmar’s works

Cette thèse propose une lecture transgénérique de l’œuvre de la poétesse judéo-allemande Gertrud Kolmar (1894-1943) au prisme de l’identité juive et de l’altérité. Cette recherche s’appuie sur un corpus incluant le roman Die jüdische Mutter, la nouvelle Susanna, les pièces de théâtre Möblierte Dame et Nacht, plusieurs recueils de poèmes dont Weibliches Bildnis, Das Wort der Stummen et Welten ainsi que la correspondance entretenue par l’auteure avec sa sœur Hilde Wenzel. En s’appuyant sur une analyse des textes et sur une contextualisation littéraire et historique de l’époque de Kolmar, ce travail révèle le positionnement singulier de l’auteure par rapport à la question de la judéité mais aussi par rapport à d’autres identités marginalisées. L’œuvre témoigne d’un regard critique sur le judaïsme ouest-européen et appelle de ses vœux un judaïsme jugé plus « authentique », proche de l’Europe de l’Est. Cette réaffirmation identitaire convoque entre autres la figure de l’Ostjude et des figures bibliques. En interrogeant le lien entre identité et espace, l’analyse invite à lire l’œuvre comme un glissement d’Ouest en Est, de Berlin devenu un espace impossible vers un Orient fantasmé, et comme une recherche de nouveaux espaces, concrets et imaginaires, par une auteure juive qui subit les persécutions antisémites et voit son propre espace se restreindre. En témoignant des violences subies par les Juifs d’Allemagne, Kolmar développe des nouvelles représentations de l’identité juive face à l’antisémitisme et à la « haine de soi ».This thesis is based on a close reading of the Jewish-German poet Gertrud Kolmar’s works (1894-1943) and through the lens of Jewish identity and otherness. The research is based on a corpus that includes the novel Die jüdische Mutter, the novella Susanna, the plays Möblierte Dame (mit Küchenbenutzung) and Nacht, several poetry cycles such as Weibliches Bildnis, Das Wort der Stummen, Welten, and the epistolary exchange between the author and her sister Hilde Wenzel. By drawing on a close analysis of the texts and exploring the literary and historical context of Kolmar’s time, this thesis shows the singularity of Kolmar’s position on Jewishness and on other forms of marginal identities. The works display a critical point of view towards Western-European Judaism and call for what would be perceived as a more “authentic” Judaism, associated with Eastern Europe. The reassertion of Jewish identity is emphasized by calling on figures like the Ostjude or biblical figures. By confronting the notions of space and identity, this research perceives the works as a shift from West to East, from Berlin – an “impossible” space – to a fantasized Orient, and as a search for new spaces, concrete and imaginary, by a Jewish author who is a victim of anti-Semitic persecution and sees her own space shrink. Through her account of the violence inflicted on German Jews, Kolmar develops new representations of Jewish identity in order to cope with antisemitism and “self-hatred”.Diese Dissertation beruht auf einer transgenerischen Analyse des Werks der Dichterin Gertrud Kolmar (1894-1943) in Bezug auf jüdische Identitäten und Figuren des Anderen. Die Analyse stützt sich auf einen Korpus aus dem Roman Die jüdische Mutter, der Novelle Susanna, den Theaterstücken Möblierte Dame (mit Küchenbenutzung) und Nacht, den Gedichtzyklen Weibliches Bildnis, Das Wort der Stummen, Welten sowie den Briefen an die im Exil lebende Schwester Hilde Wenzel. Anhand einer textimmanenten Analyse sowie einer literarischen und historischen Kontextualisierung der Epoche Kolmars entsteht das Bild einer eigenwilligen Verortung Kolmars gegenüber Paradigmen wie Jüdischkeit oder anderen Außenseiter-Identitäten. Das Werk zeugt von einem kritischen Blickwinkel auf das westeuropäische Judentum und einer Standortverlagerung zugunsten des osteuropäischen Judentums, das als ,,authentischer” wahrgenommen wird. Diese Identitätsbehauptung beruht unter anderem auf der Figur des Ostjuden oder auf biblischen Vorbildern. Diese Studie artikuliert Identitäts- und Raumbegriff und begreift das Werk als eine geistige Standortverlagerung von West nach Ost, von Berlin, einem für jüdische Autoren verbotenen Raum, bis hin zu einem fantasierten Orient, und als eine Suche nach neuen Räumen, seien sie konkret oder imaginär, einer jüdischen Autorin, deren Handlungsspielraum immer mehr eingegrenzt wird. Als Zeugin der Verfolgung der deutschen Juden greift Kolmar auf neue Darstellungen jüdischer Identität angesichts Antisemitismus und ,,Selbsthass” zurück

Mortalidade por melanoma no Estado do Rio Grande do Sul

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Mortalidade por melanoma no Estado do Rio Grande do Sul

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