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

Optimising a targeted test reduction intervention for patients admitted to the intensive care unit: the Targeted Intensive Care Test Ordering Cluster Trial intervention

Abstract not available.Edward Litton, Helen Atkinson, James Anstey, Matthew Anstey, Lewis T. Campbell, Andrew Forbes, Rebecca Hahn, Katherine Hooper, Jessica Kasza, Sharon Knapp, Forbes McGain, Nhi Ngyuen, David Pilcher, Benjamin Reddi, Chris Reid, Suzanne Robinson, Kelly Thompson, Steve Webb, Paul Youn

Fire and Nitrogen Alter Axillary Bud Number and Activity in Purple Threeawn

Belowground accumulation of vegetative buds provides a reservoir of meristems that can be utilized following disturbance. Perennial grass bud banks are the primary source of nearly all tiller growth, yet understanding of fire and nitrogen effects on bud banks is limited. We tested effects of fire and nitrogen addition on bud banks of purple threeawn (Aristida purpurea Nutt.), a perennial C4 bunchgrass. Fire (no fire, summer fire, fall fire) and nitrogen addition (0,46, 80 kg·ha-1) treatments were assigned in a completely randomized, fully factorial design and axillary buds were evaluated on two similar sites in southeastern Montana 1 and 2 years after fire. Permanently marked plants were assessed for live tiller production, and randomly selected tillers were sampled to determine active and dormant buds per tiller. Fire and nitrogen had opposite effects on axillary buds. Summer and fall fire reduced active buds by 42% relative to nonburned plots. Adding nitrogen at 46 or 80 kg.ha-1 increased active buds per tiller 60% compared with plots with no nitrogen addition. The number of dormant buds per tiller was similar across fire treatments and levels of nitrogen. Fire and nitrogen had interacting effects on total buds at the tiller level. Without nitrogen addition, fall and summer fire reduced total buds per tiller about 70%. Nitrogen had no effect on total buds per tiller for nonburned plants. However, total number of buds per tiller was greater with nitrogen addition following fall fire and increased with each increase in nitrogen following summer fire. Results indicate fire effectively controls purple threeawn through bud bank reduction and that nitrogen can stimulate bud production. Interacting effects of fire and nitrogen on buds reveal a potential source of inconsistency in nitrogen effects and a possible method of facilitating recovery of fire-sensitive bunchgrasses after fire. © 2015 Society for Range Management. Published by Elsevier Inc. All rights reserved.The Rangeland Ecology & Management archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information