Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

evidence from electrophysiological and vascular responses

Die Phonotaktik ist das jeder Sprache zugrunde liegende Regelmuster bestimmter Lautkombinationen. Jede Sprache verfügt über eigene phonotaktische Regeln (die Kombination der Buchstaben „fr“ ist im Deutschen beispielsweise möglich wie im Wort „Frage“, die Kombination der Buchstaben „rf“ ist allerdings nicht möglich.) Zur nähren Erforschung der phonotaktischen Grundlagen von Sprache dient diese Studie, die das bislang wenig erforschte Gebiet der Phonotaktik in der Sprachforschung näher beleuchten will. Methodische Grundlagen für diese Studie sind die Nahinfrarotspektroskopie (NIRS) und die Elektroenzephalographie (EEG). Erstere Methode soll hauptsächlich dazu dienen Lateralisierungseffekte in der neuronalen Verarbeitung von Phonotaktik zu untersuchen, während das EEG, welches über eine sehr gute zeitliche Auflösung verfügt, Veränderungen zeigen soll, sobald phonotaktische Regeln neuronal erkannt und verarbeitet werden. Folgende Ergebnisse können in der durchgeführten Studie festgehalten werden: • EEG/ERP: Es kann eine zentral lokalisierte N400 Komponente bei der Verarbeitung von legalen (deutschen) Pseudowörtern gezeigt werden, die sich insbesondere auf die Elektroden Cz, CPz und Pz bezieht. Für illegale Pseudowörter kann nur eine weniger stark ausgeprägte N400 Komponente festgestellt werden. • EEG/ERP: Bei den erwachsenen Probanden zeigt sich kein signifikanter Unterschied in der neuronalen Verarbeitung von Adult directed speech im Gegensatz zu Infant directed speech. • NIRS: Es zeigt sich eine signifikante Interaktion zwischen der Verarbeitung von legalen (deutschen) Pseudowörtern und dem Abfall der [deoxy-Hb]-Konzentration auf der linken Hemisphäre. Dies spricht für eine verstärkte Aktivität der linken Hemisphäre beim Verarbeiten von legalen Pseudowörtern. Für die illegalen (slowakischen) Pseudowörter zeigen sich hingegen marginal signifikante Interaktionen für die rechtshemisphärische Verarbeitung. • NIRS: Für die Verarbeitung von Adult directed speech und Infant directed speech zeigen sich keine signifikanten Unterschiede in der Verarbeitung und keine Lateralisierungseffekte. Die Studie legt nahe, dass Erwachsene die in ihrer Muttersprache vorkommenden phonotaktischen Regeln anders verarbeiten als phonotaktische Regeln, die in dieser Sprache nicht vorkommen. Es kann gezeigt werden, dass legale phonotaktische Regeln zu einer verstärkten neuronalen Aktivierung führen, die bei illegalen Pseudowörtern ausbleibt. Weiterhin kann eine linkshemisphärische Dominanz für die Verarbeitung von legalen Pseudowörtern gezeigt werden, wie sie nach dem AST- Modell (Poeppel 2003)zu erwarten war. Ein weiteres Ziel der Studie ist es zu untersuchen, ob Adult directed speech und Infant directed speech von erwachsenen Probanden unterschiedlich verarbeitet werden. Nach den in dieser Studie gewonnenen Ergebnissen ist dies nicht zu bestätigen. Eine weitere sinnvolle Fortführung dieser Studie ist die Anwendung desselben Versuchsdesigns auf Kinder. Dabei bieten sich Studien an Neugeborenen, Säuglingen und Kleinkindern an, um den Verlauf der phonotaktischen Sprachentwicklung beurteilen zu können. Darüber hinaus wäre es bei der Untersuchung von Kindern auch möglich, die unterschiedliche Verarbeitung von Pseudowörtern in Adult directed speech und Infant directed speech zu bewerten.Spoken word recognition is achieved via competition between activated lexical candidates that match the incoming speech input. The competition is modulated by prelexical cues that are important for segmenting the auditory speech stream into linguistic units. One such prelexical cue that listeners rely on in spoken word recognition is phonotactics. Phonotactics defines possible combinations of phonemes within syllables or words in a given language. The present study aimed at investigating both temporal and topographical aspects of the neuronal correlates of phonotactic processing by simultaneously applying event-related brain potentials (ERPs) and functional near-infrared spectroscopy (fNIRS). Pseudowords, either phonotactically legal or illegal with respect to the participants’ native language, were acoustically presented to passively listening adult native German speakers. ERPs showed a larger N400 effect for phonotactically legal compared to illegal pseudowords, suggesting stronger lexical activation mechanisms in phonotactically legal material. fNIRS revealed a left-hemispheric network including fronto-temporal regions with greater response to phonotactically legal pseudowords than to illegal pseudowords. This confirms earlier hypotheses on a left-hemispheric dominance of phonotactic processing most likely due to the fact that phonotactics is related to phonological processing and represents a segmental feature of language comprehension. These segmental linguistic properties of a stimulus are predominantly processed in the left hemisphere. Thus, our study provides first insights into temporal and topographical characteristics of phonotactic processing mechanisms in a passive listening task. Differential brain responses between known and unknown phonotactic rules thus supply evidence for an implicit use of phonotactic cues to guide lexical activation mechanisms

Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma

Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma. As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required. Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples. We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age- and sex-matched healthy controls. Tumor volumes were measured in MRI data using an artificial neural network-based approach. MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue. Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma. Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels. Surprisingly, the levels of Trp metabolites were also reduced. The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites. High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival. MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues. Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation. Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset.Conclusion: The novel techniques we developed could support the identification of patients that may benefit from therapies targeting TCEs or AHR activatio

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries