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

Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

Altres ajuts: Max Planck Society (Germany).The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes

SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.

COVID-19-induced “acute respiratory distress syndrome” (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS

SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis

COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS

Genetic Engineering and Nitrogen Fixation

Nitrogen is extremely important in agriculture because it is a constituent of proteins, nucleic acids and other essential molecules in all organisms. Most of this nitrogen is derived from reduced or oxidized forms of N in the soil by growing plants, because plants and animals are unable to utilize N2, which is abundant in the atmosphere. Under most cropping conditions N is limiting for growth and is provided in fertilizers, usually at rates of between 50 and 300 kg of N per ha per year (Anonymous, 1979). The only other sources available to plants are from decomposing organic matter, soil reserves, biological nitrogen fixation, the little that is deposited in rainfall and from other sources such as automobile exhausts. Biological nitrogen fixation, the enzymic conversion of N2 gas to ammonia, is much the most important source of fixed nitrogen entering those soils which receive less than about 5 kg N per ha per year from fertilizers. The reduction of N2 is catalysed by the nitrogenase system, which is very similar in composition and function in all prokaryotes which produce it Indeed, subunits of nitrogenase obtained from different nitrogen-fixing species can often be mixed to produce a functional system (Emerich and Burris, 1978). In addition, DNA coding for the structural proteins is so highly conserved in sequence that this coding has been used in hybridization experiments to demonstrate the presence of these genes in all nitrogen-fixing species of prokaryotes tested (Mazur, Rice and Haselkorn, 1980; Ruvkun and Ausubel, 1980). Nitrogenase is found only in prokaryotic micro-organisms and thus eukaryotes, such as plants!» can benefit from N2 fixation only jf they interact with N2-fixing species of micro-organism or obtain the fixed N after the death of the organisms. Nitrogenase functions only under anaerobic conditions because it is irreversibly inactivated by oxygen. The fixation ofN2 requires large amounts of energy, about 30 moles of ATP per mole N2 reduced (Hill, 1976; Schubert and Wolk, 1982), and thus can act as a major drain for energy produced by N2-fixing micro-organisnls. The requirement for an anaerobic environment and large amounts of energy presents problems to the micro-organisms that fix N2 and to the geneticists who wish to extend the range of N2..fixing organisms. Many micro..organisms fix N2 anaerobically and thus avoid the oxygen problem. However, energy production from organic compounds is usually much more efficient when they are metabolized by oxidative phosphorylation. Thus, in general, nitrogen fixation under aerobic or microaerobic conditions should be more efficient, unless too much energy is lost in protecting the enzyme from oxygen or replacing oxygen-damaged proteins. An important consequence of the large energy cost for biological nitrogen fixation is that the activity of nitrogenase needs to be regulated very carefully to ensure that only the required amount of fixed N is produced. We discuss the regulation of N2 fixation in Klebsiella pneumoniae in some detail in this chapter because a full understanding of how nitrogenase is regulated will be necessary if the transfer of N 2 fixation genes (nij') into other species, or even plants, is to be beneficial to the recipient organism. The preceding remarks about the energy requirement and oxygen stability of nitrogenase point to two of the most important problems that will be faced in transferring nij"genes to new hosts. In this review we will discuss other potential problems and show how our knowledge of the genetics of nitrogen fixation might be exploited in future