Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Nutzung von Routinedaten aus Notaufnahmen zur Surveillance von Suizidversuchen und psychiatrischen Notfällen

Hintergrund: Die Häufigkeit von Suizidversuchen ist ein zentraler Indikator der psychischen Gesundheit der Bevölkerung und daher Gegenstand der Mental Health Surveillance am Robert Koch-Institut. Da bisher keine Datenquellen systematisch zur kontinuierlichen Erfassung von psychiatrischen Notfällen - zu denen Suizidversuche zählen - herangezogen werden, wird die Nutzung von Routinedaten aus Notaufnahmen zu diesem Zweck geprüft. Methoden: Routinedaten aus 12 Notaufnahmen wurden für den Zeitraum 01.01.2018-28.03.2021 ausgewertet. Syndromdefinitionen für Suizidversuche, psychiatrische Notfälle und psychische Symptomatik wurden als Kombinationen aus Vorstellungsgründen und Diagnosen entwickelt. Fälle wurden alters- und geschlechtsspezifisch sowie im Zeitverlauf dargestellt. Ergebnisse: Von insgesamt 1.516.883 Notaufnahmevorstellungen wurden 5133 (0,3 %) als Suizidversuche, 31.085 (2,1 %) als psychiatrische Notfälle und 34.230 (2,3 %) als Fälle mit einer psychischen Symptomatik identifiziert. 16,5 % der psychiatrischen Notfälle wurden so als Suizidversuch eingeschätzt. Unter den Suizidversuchen entfallen 53,4 % auf Männer und insgesamt 20,2 % auf die Altersgruppe der 25- bis 34-Jährigen. Alle 3 Syndromdefinitionen können über den gesamten Beobachtungszeitraum Fälle sowie deren zeitliche Variation abbilden. Fazit: Notaufnahmedaten zeigen Potenzial zur syndromischen Surveillance von Suizidversuchen und psychiatrischen Notfällen und bieten damit einen Ausgangspunkt für weitere Validierung und Analyse. Die Abbildung von Veränderungen in Echtzeit erweitert die bisherigen Forschungsmöglichkeiten zu psychiatrischen Notfällen in Deutschland. Eine systematische Surveillance von Suizidversuchen kann zu einer evidenzbasierten Suizidprävention beitragen

Polygenic risk for schizophrenia affects working memory and its neural correlates in healthy subjects

Schizophrenia is a disorder with a high heritability. Patients as well as their first degree relatives display lower levels of performance in a number of cognitive domains compared to subjects without genetic risk. Several studies could link these aberrations to single genetic variants, however, only recently, polygenic risk scores as proxies for genetic risk have been associated with cognitive domains and their neural correlates. In the present study, a sample of healthy subjects (n=137) performed a letter version of the n-back task while scanned with 3-T fMRI. All subjects were genotyped with the PsychChip and polygenic risk scores were calculated based on the PGC2 schizophrenia GWAS results. Polygenic risk for schizophrenia was associated with a lower degree of brain activation in prefrontal areas during the 3-back compared to the 0-back baseline condition. Furthermore, polygenic risk was associated with lower levels of brain activation in the right inferior frontal gyrus during the 3-back compared to a 2-back condition. Polygenic risk leads to a shift in the underlying activation pattern to the left side, thus resembling results reported in patients with schizophrenia. The data may point to polygenic risk for schizophrenia being associated with brain function in a cognitive task known to be impaired in patients and their relatives

Electroconvulsive therapy modulates grey matter increase in a hub of an affect processing network

A growing number of recent studies has suggested that the neuroplastic effects of electroconvulsive therapy (ECT) might be prominent enough to be detected through changes of regional gray matter volumes (GMV) during the course of the treatment. Given that ECT patients are difficult to recruit for imaging studies, most publications, however, report only on small samples. Addressing this challenge, we here report results of a structural imaging study on ECT patients that pooled patients from five German sites. Whole-brain voxel-based morphometry (VBM) analysis was performed to detect structural differences in 85 patients with unipolar depression before and after ECT, when compared to 86 healthy controls. Both task-independent and task-dependent physiological whole-brain functional connectivity patterns of these regions were modeled using additional data from healthy subjects. All emerging regions were additionally functionally characterized using the BrainMap database. Our VBM analysis detected a significant increase of GMV in the right hippocampus/amygdala region in patients after ECT compared to healthy controls. In healthy subjects this region was found to be enrolled in a network associated with emotional processing and memory. A region in the left fusiform gyrus was additionally found to have higher GMV in controls when compared with patients at baseline. This region showed minor changes after ECT. Our data points to a GMV increase in patients post ECT in regions that seem to constitute a hub of an emotion processing network. This appears as a plausible antidepressant mechanism and could explain the efficacy of ECT not only in the treatment of unipolar depression, but also of affective symptoms across heterogeneous disorders

Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies

Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.ISSN:0304-3835ISSN:1872-798