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

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

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

Measurement of CP asymmetries and branching fraction ratios of B− decays to two charm mesons

The $CP$ asymmetries of seven $B^-$ decays to two charm mesons are measured using data corresponding to an integrated luminosity of $9\text{fb}^{-1}$ of proton-proton collisions collected by the LHCb experiment. Decays involving a $D^{*0}$ or $D^{*-}_s$ meson are analysed by reconstructing only the $D^0$ or $D^-_s$ decay products. This paper presents the first measurement of $\mathcal{A}^{CP}(B^- \rightarrow D^{*-}_s D^0)$ and $\mathcal{A}^{CP}(B^- \rightarrow D^{-}_s D^{*0})$, and the most precise measurement of the other five $CP$ asymmetries. There is no evidence of $CP$ violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.The CP asymmetries of seven B$^{−}$ decays to two charm mesons are measured using data corresponding to an integrated luminosity of 9 fb$^{−1}$ of proton-proton collisions collected by the LHCb experiment. Decays involving a D$^{*0}$ or ${D}_s^{\ast -}$ meson are analysed by reconstructing only the D$^{0}$ or ${D}_s^{-}$ decay products. This paper presents the first measurement of $\mathcal{A} ^{CP}$(B$^{−}$→${D}_s^{\ast -}$D$^{0}$) and $\mathcal{A} ^{CP}$(B$^{−}$→${D}_s^{-}$D$^{∗0}$), and the most precise measurement of the other five CP asymmetries. There is no evidence of CP violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.[graphic not available: see fulltext]The $CP$ asymmetries of seven $B^-$ decays to two charm mesons are measured using data corresponding to an integrated luminosity of $9\text{ fb}^{-1}$ of proton-proton collisions collected by the LHCb experiment. Decays involving a $D^{*0}$ or $D^{*-}_s$ meson are analysed by reconstructing only the $D^0$ or $D^-_s$ decay products. This paper presents the first measurement of $\mathcal{A}^{CP}(B^- \rightarrow D^{*-}_s D^0)$ and $\mathcal{A}^{CP}(B^- \rightarrow D^{-}_s D^{*0})$, and the most precise measurement of the other five $CP$ asymmetries. There is no evidence of $CP$ violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured

Helium identification with LHCb

The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using pp collision data at √(s) = 13 TeV recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of 5.5 fb-1. A total of around 105 helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately 50% with a corresponding background rejection rate of up to O(10^12). These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei

Curvature-bias corrections using a pseudomass method

Momentum measurements for very high momentum charged particles, such as muons from electroweak vector boson decays, are particularly susceptible to charge-dependent curvature biases that arise from misalignments of tracking detectors. Low momentum charged particles used in alignment procedures have limited sensitivity to coherent displacements of such detectors, and therefore are unable to fully constrain these misalignments to the precision necessary for studies of electroweak physics. Additional approaches are therefore required to understand and correct for these effects. In this paper the curvature biases present at the LHCb detector are studied using the pseudomass method in proton-proton collision data recorded at centre of mass energy √(s)=13 TeV during 2016, 2017 and 2018. The biases are determined using Z→μ + μ - decays in intervals defined by the data-taking period, magnet polarity and muon direction. Correcting for these biases, which are typically at the 10-4 GeV-1 level, improves the Z→μ + μ - mass resolution by roughly 18% and eliminates several pathological trends in the kinematic-dependence of the mean dimuon invariant mass

Momentum scale calibration of the LHCb spectrometer

For accurate determination of particle masses accurate knowledge of the momentum scale of the detectors is crucial. The procedure used to calibrate the momentum scale of the LHCb spectrometer is described and illustrated using the performance obtained with an integrated luminosity of 1.6 fb-1 collected during 2016 in pp running. The procedure uses large samples of J/ψ → μ + μ - and B+ → J/ψ K + decays and leads to a relative accuracy of 3 × 10-4 on the momentum scale

The synthesis and molecular and crystal structures of 1-methyl-2-carboxy-1,2-dicarba-closo-dodecaborane(12), 1-phenyl-2-carboxy-1,2-dicarba-closo-dodecaborane(12) and 1-phenyl-2-benzoyl-1,2-dicarba-closo-dodecaborane(12)

The structures of 1-Me-2-COOH-1,2-closo-C2B10H10 (1), 1-Ph-2-COOH-1,2-closo-C2B10H10 (2) and 1-Ph-2-COPh-1,2-closo-C2B10H10 (3) have been determined by X-ray crystallography. In 1 the orientation of the COOH group is defined by theta(COOH) = 65.0(2)(syn)degrees, and this group H-bonds to that in a second molecule via a centrosymmetric eight-membered ring, R-2(2)(8). DFT calculations on the parent species 1-COOH-1,2-closo-C2B10H11 reveal that the structure with theta(COOH) = 90(syn)degrees is preferred, with a barrier to COOH rotation of approximate to 17 kJ mol(-1). Similar calculations on 1 yield a lower rotational barrier, approximate to 7 kJ mol(-1), because internal H-bonding is now denied. In compound 2 the COOH group is twisted to lower theta values [5.0(3)degrees and 39.7(3)degrees] but both crystallographically independent molecules exist as dimers in the solid state by virtue of R-2(2) (8) rings. Compound 2 crystallises from wet solvent as a monohydrate, the structure of which reveals a non-planar centrosymmetric R-4(4)(12) ring and near-orthogonal Ph and COOH substituents [theta(Ph) = 6.7(2) and theta(COOH) = 78.0(2)(syn)degrees]. In compound 3 molecular association by H-bonding is blocked, so 3 serves as a useful comparative structure for 2. (C) 2003 Elsevier Ltd. All rights reserved

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

These authors contributed equally: Gail Davies, Max Lam. These authors jointly supervised this work: Todd Lencz, Ian J. Deary