Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

(17). Interestingly, the enhancement of NOS activity by NMDA stimulation of cerebellar slices also derives from channel-associated entry of calcium, which binds to calmodulin associated with NOS (9-11). To ascertain the relationship ofNO to glutamate neurotoxicity, we have employed rat primary cortical cultures and demonstrate that glutamate neurotoxicity is prevented selectively by inhibitors of NOS. MATERIALS AND METHODSCell Culture. Primary dissociated cell cultures were prepared from fetal rats (13-to 14-day gestation for cortex and caudate-putamen cultures and 19-to 20-day gestation for hippocampal cultures). The tissue of interest was dissected, incubated for 15 min in 0.027% trypsin in Brooks-Logan solution (5% phosphate-buffered saline/0.04 M sucrose/10 mM Hepes/0.03 M glucose, pH 7.4), and then transferred to modified Eagle's medium (MEM)/10%o horse serum/10%o fetal bovine serum/2 mM glutamine for trituration. Dissociated cells were plated at a density of 3-4 x 105 cells per well in polyornithine-coated 15-mm multiwell plates. After 4 days the cells were treated with 10 ,g of 5-fluoro-2'-deoxyuridine to prevent proliferation of nonneuronal cells. Cells were maintained in MEM/5% horse serum/2 mM glutamine in 8% C02/humidified atmosphere at 37°C. The medium was changed twice weekly. In the present study, mature neurons (3-4 weeks) were used.Cytoxicity. Cells were exposed to excitatory amino acids according to the method of Koh and Choi (18). Before exposure, the cells were washed three times with Trisbuffered control salt solution (CSS) (18), containing 120 mM NaCl/5.4 mM KCl/1.8 mM CaCI2/25 mM Tris hydrochloride, pH 7.4 at room temperature/15 mM glucose). Brief exposures to glutamate, NMDA (plus 10 ,uM glycine), quisqualate, and sodium nitroprusside (SNP) were performed for 5 min in CSS. The exposure solution was then washed away and replaced by MEM with 21 mM glucose; then the cells were placed in an incubator for 20-24 hr. Long exposures to kainate were performed in MEM/21 mM glucose for 20-24 hr in the incubator. After exposure to the excitatory amino acids, the medium was replaced by CSS/0.4% trypan blue, which stains nonviable cells. Two to four photographs (10-20x) were made of each well, and viable versus nonviable cells were counted. The cytotoxicity data represent 6-24 separate wells assayed per data point, with -500-1500 cells counted per well. In some experiments, overall neuronal cell injury was also assessed by the measurement of lactate

Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.Most individuals who suffer from dependence on cocaine and other addictive drugs return to substance abuse within a year of initiating abstinence (1, 2). Addicts often attribute relapse to intense desire or "craving," which may arise in an environment associated with drug use (3-5). Moreover, drug-related cues can induce craving in laboratory settings (6-8). Substantial interest focuses on the mechanisms by which drug-related stimuli elicit craving (3, 5, 9-12) despite concerns that craving does not inevitably lead to drug taking (13). Little is known, however, about the biological basis of cue-elicited drug craving, except that cocaine users exposed to drug-related cues exhibit diffuse decreases in the power of the electroencephalogram (8). The purpose of the present study was to identify brain regions that mediate cue-elicited cocaine craving. To this end, regional cerebral metabolic rate for glucose (rCMRglc), an index of local brain function (14, 15), was measured in cocaine abusers and normal volunteers in a neutral test session and in another session during which cocaine-related stimuli were presented. METHODS Subjects. Thirteen cocaine abusers (COC group; 25-42 years old; 12 men, 1 woman; 12 Black, 1 White) and 5 normal volunteers (24-29 years old; 4 men, 1 woman; all Black) participated in the study. Evidence of physical disease, history of head trauma with loss of consciousness, or fulfillment of criteria for any axis I psychiatric diagnosis other than substance abuse or dependence or for any axis II disorder other than borderline or antisocial personality disorder were exclusionary criteria (16). Subjects in the COC group reported long-term cocaine use (median 8 years; range 2.5-20 years) with a current median use of 2.5 g/week (range 0.2-4.3 g/week). They also reported using opiates (5/13 subjects), marijuana (9/13), alcohol (13/13), and nicotine (11/13), but were not physically dependent on opiates or alcohol, nor were any of them receiving treatment for drug abuse. Some control subjects used nicotine (3/5), and alcohol (3/5); one reported a single use of marijuana more than a decade before the study. All volunteers in both groups had been abstinent from nicotine, alcohol, and caffeine for 12-15 h prior to each test session. Eight...

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.