Common aetiology for diverse language skills in 41/2-year-old twins

Multivariate genetic analysis was used to examine the genetic and environmental aetiology of the interrelationships of diverse linguistic skills. This study used data from a large sample of 4 1/2 year-old twins who were tested on measures assessing articulation, phonology, grammar, vocabulary, and verbal memory. Phenotypic analysis suggested two latent factors: articulation (2 measures) and general language (the remaining 7), and a genetic model incorporating these factors provided a good fit to the data. Almost all genetic and shared environmental influences on the 9 measures acted through the two latent factors. There was also substantial aetiological overlap between the two latent factors, with a genetic correlation of 0·64 and shared environment correlation of 1·00. We conclude that to a large extent, the same genetic and environmental factors underlie the development of individual differences in a wide range of linguistic skills

True Grit and Genetics: Predicting Academic Achievement from Personality

Grit -- perseverance and passion for long-term goals -- has been shown to be a significant predictor of academic success, even after controlling for other personality factors. Here, for the first time, we use a UK-representative sample and a genetically sensitive design to unpack the etiology of grit and its prediction of academic achievement in comparison to well-established personality traits. For 4,642 16-year-olds (2,321 twin pairs), we used the Grit-S scale (Perseverance of Effort and Consistency of Interest), along with the Big-5 personality traits, to predict scores on the General Certificate of Secondary Education (GCSE) exams, which are administered UK-wide at the end of compulsory education. Twin analyses of Grit Perseverance yielded a heritability estimate of 37% (20% for Consistency of Interest) and no evidence for shared environmental influence. Personality, primarily Conscientiousness, predicts about 6% of the variance in GCSE scores, but Grit adds little to this prediction. Moreover, multivariate twin analyses showed that roughly two-thirds of the GCSE prediction is mediated genetically. Grit Perseverance of Effort and Big-5 Conscientiousness are to a large extent the same trait both phenotypically (r=0.53) and genetically (genetic correlation = 0. 86). We conclude that the etiology of Grit is highly similar to other personality traits, not only in showing substantial genetic influence but also in showing no influence of shared environmental factors. Personality significantly predicts academic achievement, but Grit adds little phenotypically or genetically to the prediction of academic achievement beyond traditional personality factors, especially Conscientiousness

ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm

The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co-immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated

Language profiles and literacy outcomes of children with resolving, emerging, or persisting language impairments

Background: Children with language impairment (LI) show heterogeneity in development. We tracked children from pre-school to middle childhood to characterize three developmental trajectories: resolving, persisting and emerging LI. Methods: We analyzed data from children identified as having preschool LI, or being at family risk of dyslexia, together with typically developing controls at three time points: t1 (age 3;09), t3 (5;08) and t5 (8;01). Language measures are reported at t1, t3 and t5, and literacy abilities at t3 and t5. A research diagnosis of LI (irrespective of recruitment group) was validated at t1 by a composite language score derived from measures of receptive and expressive grammar and vocabulary; a score falling 1SD below the mean of the typical language group on comparable measures at t3 and t5 was used to determine whether a child had LI at later time points and then to classify LIs as resolving, persisting or emerging. Results: Persisting preschool LIs were more severe and pervasive than resolving LIs. Language and literacy outcomes were relatively poor for those with persisting LI, and relatively good for those with resolving LI. A significant proportion of children with average language abilities in preschool had LIs that emerged in middle childhood - a high proportion of these children were at family risk of dyslexia. There were more boys in the persisting and resolving LI groups. Children with early LIs which resolved by the start of formal literacy instruction tended to have good literacy outcomes; children with late-emerging difficulties that persisted developed reading difficulties. Conclusions: Children with late-emerging LI are relatively common and are hard to detect in the preschool years. Our findings show that children whose LIs persist to the point of formal literacy instruction frequently experience reading difficulties

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients

The Physics of Star Cluster Formation and Evolution

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00689-4.Star clusters form in dense, hierarchically collapsing gas clouds. Bulk kinetic energy is transformed to turbulence with stars forming from cores fed by filaments. In the most compact regions, stellar feedback is least effective in removing the gas and stars may form very efficiently. These are also the regions where, in high-mass clusters, ejecta from some kind of high-mass stars are effectively captured during the formation phase of some of the low mass stars and effectively channeled into the latter to form multiple populations. Star formation epochs in star clusters are generally set by gas flows that determine the abundance of gas in the cluster. We argue that there is likely only one star formation epoch after which clusters remain essentially clear of gas by cluster winds. Collisional dynamics is important in this phase leading to core collapse, expansion and eventual dispersion of every cluster. We review recent developments in the field with a focus on theoretical work.Peer reviewe

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

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