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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Formation of the Cortical Subventricular Zone Requires MDGA1-Mediated Aggregation of Basal Progenitors

The subventricular zone (SVZ) provides a specialized neurogenic microenvironment for proliferation and aggregation of basal progenitors (BPs). Our study reveals a mechanism for the aggregation of BPs within the SVZ required for their proliferation and generation of cortical layer neurons. The autism-related IgCAM, MDGA1, is locally expressed in the BP cell membrane where it co-localizes and complexes with the gap junction protein Connexin43. To address MDGA1 function, we created a floxed allele of MDGA1 and deleted it from BPs. MDGA1 deletion results in reduced BP proliferation and size of the SVZ, with an aberrant population of BPs ectopically positioned in the cortical plate. These defects are manifested in diminished production of cortical layer neurons and a significant reduction of the cortical layers. We conclude that MDGA1 functions to aggregate and maintain BPs within the SVZ providing the neurogenic niche required for their proliferation and generation of cortical layer neurons

Summary of the expression analyses used to define the inhibitory or excitatory phneotype of postnatal neurons that express Pax2, Gbx1, Lmx1b, RORβ, RORα, Lbx1, MafA, MafB and c-Maf.

<p>Pax2 and Gbx1 are inhibitory markers, whereas Lmx1b and MafA are excitatory markers. Lbx1 and RORα predominantly label excitatory neurons, as well as a small number of inhibitory neurons. MafB and c-Maf are expressed by mixed populations of inhibitory and excitatory neurons. Data is expressed as mean±s.d. RORα expression was analyzed using a <i>RORα</i>^Cre; <i>R26</i>^{floxstop-Tomato} reporter. Asterisk indicates 100% by definition.</p

Comparative expression of transcription factors that are co-localized with the excitatory marker Lmx1b.

<p>Lbx1, RORα, RORβ, MafA, MafB and c-Maf all show overlapping expression with Lmx1b in excitatory neurons, albeit at low levels in some neurons. Analyses were performed at P0 (C–D, K–L), P7 (I–J, G–H), P8 (E–F) and P10 (A–B). Neurons were assigned a cell type number (1–9) according to their expression profile, with profiles 1–5 being classified as inhibitory neurons, while profiles 6–9 are excitatory neurons (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077928#pone-0077928-t002" target="_blank">Table 2</a>).</p

Comparison of transcription factor expression with inhibitory neuronal markers.

<p>Lbx1 (A–D), RORβ (E–H), MafB (I–L) and c-Maf (M–P) are expressed in many neurons that express the inhibitory markers Gbx1 (C–D, G–H, K–L, O–P, V–W), <i>GAD67-GFP</i> (A–B, M–N) and <i>Pax2-Cre; R26</i>^floxstop-GFP (E–F, I–J). In <i>RORα-Cre; R26</i>^{floxstop-Tomat<i>o</i>} mice (V–W), we observed a few Tomato⁺ neurons that expressed Gbx1. MafA is the only transcription factor that did not co-localize with Gbx1 (S–T) or GFP in <i>GAD67-GFP</i> and <i>Pax2-Cre; R26</i>^floxstop-GFP mice (Q-R, data not shown). <i>Pax2-Cre; R26GFP</i> denotes GFP⁺ cells in <i>Pax2-Cre; R26</i>^floxstop-GFPmice. Spinal cords were analyzed at P0 (E–F), P1 (C–D, I–J, S–T), P2 (G–H), P7 (A–B, M–N, Q–R), P8 (V–W), and P10 (K–L, O–P). Examples of the nine different cell types (numbered 1–9) are shown. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077928#pone-0077928-t002" target="_blank">Table 2</a> for further details.</p