Showing papers by "Edythe D. London published in 2017"
North Shore-LIJ Health System1, Yale University2, University of Edinburgh3, Oslo University Hospital4, University of Bergen5, University of Oslo6, Haukeland University Hospital7, University of Helsinki8, Wellcome Trust Sanger Institute9, Martin Luther University of Halle-Wittenberg10, Icahn School of Medicine at Mount Sinai11, Veterans Health Administration12, University of Crete13, University of Manchester14, Manchester Academic Health Science Centre15, Duke University16, Imperial College London17, Centre for Addiction and Mental Health18, Mental Health Research Institute19, National and Kapodistrian University of Athens20, Johns Hopkins University21, Semel Institute for Neuroscience and Human Behavior22, Stanford University23, University of Oregon24, National Institutes of Health25, National University of Ireland, Galway26, Trinity College, Dublin27, University of Colorado Boulder28, Hofstra University29
TL;DR: Common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% for general cognitive function, which provides new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
Abstract: The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
196 citations
North Shore-LIJ Health System1, Yale University2, University of Edinburgh3, Oslo University Hospital4, University of Bergen5, University of Oslo6, Haukeland University Hospital7, University of Helsinki8, Wellcome Trust Sanger Institute9, Martin Luther University of Halle-Wittenberg10, Veterans Health Administration11, Icahn School of Medicine at Mount Sinai12, University of Crete13, University of Manchester14, Manchester Academic Health Science Centre15, Duke University16, Imperial College London17, Centre for Addiction and Mental Health18, National and Kapodistrian University of Athens19, Mental Health Research Institute20, Johns Hopkins University21, Semel Institute for Neuroscience and Human Behavior22, Stanford University23, University of Oregon24, National Institutes of Health25, National University of Ireland, Galway26, Trinity College, Dublin27, University of Colorado Boulder28, Hofstra University29
TL;DR: In this article, the association of common genetic variation (8M single-nucleotide polymorphisms with minor allele frequency ⩾ 1%) to general cognitive function in a sample of 35,298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT) was examined.
Abstract: The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
153 citations
TL;DR: Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.
Abstract: As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system, and can induce acute psychosis, hypomania, paranoid ideation and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.
152 citations
Yale University1, University of Edinburgh2, Oslo University Hospital3, University of Oslo4, Haukeland University Hospital5, University of Bergen6, University of Helsinki7, Wellcome Trust Sanger Institute8, National Institutes of Health9, Martin Luther University of Halle-Wittenberg10, Icahn School of Medicine at Mount Sinai11, University of Crete12, University of Manchester13, Duke University14, Imperial College London15, Durham University16, Centre for Addiction and Mental Health17, National and Kapodistrian University of Athens18, Johns Hopkins University19, Johns Hopkins University School of Medicine20, Semel Institute for Neuroscience and Human Behavior21, Stanford University22, University of Oregon23, National University of Ireland, Galway24, Trinity College, Dublin25, Manchester Academic Health Science Centre26, University of Colorado Boulder27, The Feinstein Institute for Medical Research28, Hofstra University29
TL;DR: A large-scale genome-wide association study (GWAS) of general cognitive ability was presented in this paper, which showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype.
90 citations
Yale University1, University of Edinburgh2, Oslo University Hospital3, University of Oslo4, Haukeland University Hospital5, University of Bergen6, University of Helsinki7, Wellcome Trust Sanger Institute8, National Institutes of Health9, Martin Luther University of Halle-Wittenberg10, Icahn School of Medicine at Mount Sinai11, University of Crete12, University of Manchester13, Duke University14, Imperial College London15, Durham University16, Centre for Addiction and Mental Health17, National and Kapodistrian University of Athens18, Johns Hopkins University19, Johns Hopkins University School of Medicine20, Semel Institute for Neuroscience and Human Behavior21, Stanford University22, University of Oregon23, National University of Ireland, Galway24, Trinity College, Dublin25, Manchester Academic Health Science Centre26, University of Colorado Boulder27, The Feinstein Institute for Medical Research28, Hofstra University29
TL;DR: Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype and genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Abstract: Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment We identified 70 independent genomic loci associated with general cognitive ability Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum) Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth
70 citations
TL;DR: This corrects the article DOI: 10.1038/npp2017.48 to indicate that the author of the paper is a PhD student, not a professor, as previously reported.
46 citations
VU University Amsterdam1, Erasmus University Rotterdam2, Karolinska Institutet3, Charité4, Virginia Commonwealth University5, South London and Maudsley NHS Foundation Trust6, King's College London7, QIMR Berghofer Medical Research Institute8, University of Southern Denmark9, University of California, Riverside10, University of Southern California11, University of Minnesota12, University of Queensland13, Johns Hopkins University School of Medicine14, Duke University15, University of Bergen16, University of California, Los Angeles17, University of Crete18, Harvard University19, Icahn School of Medicine at Mount Sinai20, Veterans Health Administration21, Yale University22, Trinity College, Dublin23, University of Edinburgh24, Hofstra University25, North Shore-LIJ Health System26, National Institutes of Health27, University of Oslo28, National University of Ireland, Galway29, University of Helsinki30, Martin Luther University of Halle-Wittenberg31, Mental Health Research Institute32, National and Kapodistrian University of Athens33, University of Colorado Boulder34, Imperial College London35, University of Manchester36, Wellcome Trust37, Stanford University38, University of Oregon39, Johns Hopkins University40, University of Toronto41, University of Michigan42, Broad Institute43, University of North Carolina at Chapel Hill44
TL;DR: The largest genetic association study of intelligence to date is presented, identifying 206 genomic loci and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis.
Abstract: 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 intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) 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 identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimer9s dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.
32 citations
TL;DR: It is suggested that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to <0.763 mg/cigarette may contribute to temporary attentional deficits.
30 citations
TL;DR: During the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions, and hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD.
Abstract: BackgroundDifficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD.MethodsOn the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle.ResultsWomen with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants.ConclusionsDuring the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study.
26 citations
23 citations
The Feinstein Institute for Medical Research1, Yale University2, University of Edinburgh3, Oslo University Hospital4, University of Bergen5, University of Oslo6, Haukeland University Hospital7, University of Helsinki8, National Institutes of Health9, Martin Luther University of Halle-Wittenberg10, Icahn School of Medicine at Mount Sinai11, University of Crete12, Manchester Academic Health Science Centre13, University of Manchester14, Duke University15, Imperial College London16, Durham University17, Centre for Addiction and Mental Health18, National and Kapodistrian University of Athens19, Johns Hopkins University20, Johns Hopkins University School of Medicine21, Semel Institute for Neuroscience and Human Behavior22, Stanford University23, University of Oregon24, National University of Ireland, Galway25, Trinity College, Dublin26, University of Colorado Boulder27
TL;DR: The largest genome-wide association studies (GWAS) of cognitive ability to date are presented, and signal is enhanced by combining results with a large-scale GWAS of educational attainment.
Abstract: Neurocognitive ability is a fundamental readout of brain function, and cognitive deficits are a critical component of neuropsychiatric disorders, yet neurocognition is poorly understood at the molecular level. In the present report, we present the largest genome-wide association studies (GWAS) of cognitive ability to date (N=107,207), and further enhance signal by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with cognitive ability, 34 of which were novel. A total of 350 genes were implicated, and this list showed significant enrichment for genes associated with Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis of gene results implicated the biological process of neurogenesis, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker; and LY97241, a potassium channel inhibitor. Transcriptome-wide analysis revealed that the implicated genes were strongly expressed in neurons, but not astrocytes or oligodendrocytes, and were more strongly associated with fetal brain expression than adult brain expression. Several tissue-specific gene expression relationships to cognitive ability were observed (for example, DAG1 levels in the hippocampus). Finally, we report novel genetic correlations between cognitive ability and disparate phenotypes such as maternal age at first birth and number of children, as well as several autoimmune disorders.
TL;DR: The present findings provide the first direct evidence that white‐matter integrity is linked to function within previously identified components of a network that is activated during risky decision‐making, and demonstrate that the integrity ofwhite‐matter tracts is critical in consolidating and processing signals between cortical and striatal circuits during the decision-making process.
TL;DR: The results inform the interpretation of steep discounting among smokers and suggest that treatment approaches could be tailored to the type of discounting behavior that smokers exhibit.
Abstract: Background: Smokers exhibit an unusually high willingness to forgo a delayed reward of greater magnitude to receive a smaller, more immediate reward. The functional form of such “delay discounting” behavior is central to the discounting-based operationalization of impulsivity, and has implications for theories regarding the basis of steep discounting among smokers and treatment approaches to addiction. Objectives: We examined the discounting behavior of current smokers, ex-smokers, and never-smokers to determine whether the functional form of discounting differs between these groups. Methods: Participants completed a 27-item delay discounting questionnaire (25). We used finite mixture modeling in analyzing data as the product of two simultaneous data-generating processes (DGPs), a hyperbolic function and an exponential function, and compared results to a quasi-hyperbolic (QH) approximation, in a relatively large sample (n = 1205). Results: Consistent with prior reports, current smokers exhibited s...
TL;DR: The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which nALTrexone may be efficacious in treating MA use disorder.
Abstract: Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined. This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence). Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue-reactivity paradigm, and subjective response to MA was assessed during MA infusion. Cue-induced craving for MA was positively associated with post-infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving-related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue-induced craving and positive subjective response to MA. The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder.
TL;DR: Cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank were combined to find 9,714 genome-wide significant SNPs, with significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.
Abstract: General cognitive function is a prominent human trait associated with many important life outcomes including longevity. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360). We found 9,714 genome-wide significant SNPs (P
TL;DR: By far the largest ever study of cerebral cortical brain asymmetry is described, finding a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates.
Abstract: Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.