Publications by authors named "Joey W Trampush"

21 Publications

  • Page 1 of 1

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Am J Hum Genet 2019 08;105(2):334-350

Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699140PMC
August 2019

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

Nat Commun 2019 May 1;10(1):2068. Epub 2019 May 1.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-019-10160-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494826PMC
May 2019

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Nat Genet 2018 07 23;50(8):1112-1121. Epub 2018 Jul 23.

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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http://dx.doi.org/10.1038/s41588-018-0147-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393768PMC
July 2018

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Twin Res Hum Genet 2018 10 13;21(5):394-397. Epub 2018 Jul 13.

Department of Psychiatry,National and Kapodistrian University of Athens Medical School,Eginition Hospital,Athens,Greece.

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.
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http://dx.doi.org/10.1017/thg.2018.46DOI Listing
October 2018

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Nat Genet 2018 07 25;50(7):912-919. Epub 2018 Jun 25.

Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1038/s41588-018-0152-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411041PMC
July 2018

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Nat Commun 2018 05 29;9(1):2098. Epub 2018 May 29.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

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) 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.
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http://dx.doi.org/10.1038/s41467-018-04362-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974083PMC
May 2018

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Cell Rep 2017 Nov;21(9):2597-2613

Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.

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.
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http://dx.doi.org/10.1016/j.celrep.2017.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789458PMC
November 2017

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

Schizophr Res 2018 05 3;195:306-317. Epub 2017 Oct 3.

The Cognitive Genetics and Cognitive Therapy Group, Department of Psychology, National University of Ireland, Galway, Ireland.

Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection.

Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site.

Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other.

Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2017.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882601PMC
May 2018

Relationship of Cognition to Clinical Response in First-Episode Schizophrenia Spectrum Disorders.

Schizophr Bull 2015 Nov 25;41(6):1237-47. Epub 2015 Sep 25.

Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute for Medical Research, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.

First-episode schizophrenia (FES) spectrum disorders are associated with pronounced cognitive dysfunction across all domains. However, less is known about the course of cognitive functioning, following the first presentation of psychosis, and the relationship of cognition to clinical course during initial treatment. The present longitudinal study examined the magnitude of neurocognitive impairment, using the MATRICS Consensus Cognitive Battery, in patients experiencing their first episode of psychosis at baseline and after 12 weeks of randomized antipsychotic treatment with either aripiprazole or risperidone. At baseline, FES patients evidenced marked impairments in cognitive functioning. Notably, performance on the mazes task of planning and reasoning significantly predicted the likelihood of meeting stringent criteria for positive symptom remission during the first 12 weeks of the trial. Performance on indices of general cognitive function, working memory, and verbal learning improved over time, but these improvements were mediated by improvements in both positive and negative symptoms. We did not detect any differential effects of antipsychotic medication assignment (aripiprazole vs risperidone) on cognitive functioning. Our results suggest that a brief paper-and-pencil measure reflecting planning/reasoning abilities may index responsivity to antipsychotic medication. However, improvements in cognitive functioning over time were related to clinical symptom improvement, reflecting "pseudospecificity."
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http://dx.doi.org/10.1093/schbul/sbv120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601719PMC
November 2015

A Common Polymorphism in SCN2A Predicts General Cognitive Ability through Effects on PFC Physiology.

J Cogn Neurosci 2015 Sep 11;27(9):1766-74. Epub 2015 May 11.

Duke University.

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral PFC and dorsal ACC, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes interindividual variation in "g."
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http://dx.doi.org/10.1162/jocn_a_00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692714PMC
September 2015

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Am J Med Genet B Neuropsychiatr Genet 2015 Jul 7;168B(5):363-73. Epub 2015 May 7.

Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.
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http://dx.doi.org/10.1002/ajmg.b.32319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500051PMC
July 2015

Mitochondrial DNA mutations and cognition: a case-series report.

Arch Clin Neuropsychol 2014 Jun 28;29(4):315-21. Epub 2014 Apr 28.

Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.

Mutations in the mitochondrial genome can impair normal metabolic function in the central nervous system (CNS) where cellular energy demand is high. Primary mitochondrial DNA (mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae. Here, we present a series of cases with primary mtDNA mutations who were genotyped and evaluated across a common neuropsychological battery. Nineteen patients with mtDNA mutations were genotyped and clinically and cognitively evaluated. Pronounced deficits in nonverbal/visuoperceptual reasoning, verbal recall, semantic word generativity, and processing speed were evident and consistent with a "mitochondrial dementia" that has been posited. However, variation in cognitive performance was noteworthy, suggesting that the phenotypic landscape of cognition linked to primary mtDNA mutations is heterogeneous. Our patients with mtDNA mutations evidenced cognitive deficits quite similar to those commonly seen in Alzheimer's disease and could have clinical relevance to the evaluation of dementia.
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http://dx.doi.org/10.1093/arclin/acu016DOI Listing
June 2014

Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals.

JAMA Psychiatry 2014 Jun;71(6):647-56

Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland2Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland8Depar.

Importance: One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation.

Objective: To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals.

Design, Setting, And Participants: Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals.

Main Outcomes And Measures: We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts.

Results: The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects.

Conclusions And Relevance: The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.
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http://dx.doi.org/10.1001/jamapsychiatry.2014.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160812PMC
June 2014

Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development.

Dev Sci 2014 Jul 11;17(4):584-95. Epub 2014 Jan 11.

Neuropsychology Doctoral Program, Graduate Center of the City University of New York, USA; Department of Psychology, Queens College of the City University of New York, USA.

We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance and manipulation from childhood to early adulthood predicted the reduction of ADHD symptoms as a function of allelic variation in DRD1 and DRD2. Participants were 76 7-11-year-old children with ADHD who were genotyped and prospectively followed for almost 10 years. ADHD symptoms were rated using the Attention Problems scale on the Child Behavior Checklist, and verbal working memory maintenance and manipulation, measured by Digit Span forward and backward, respectively, were assessed at baseline and follow-up. After correction for multiple testing, improvements in working memory manipulation, not maintenance, predicted reduction of symptomatology over development and was moderated by major allele homozygosity in two DRD1 polymorphisms (rs4532 and rs265978) previously linked with variation in D1 receptor expression. Depending on genetic background, developmental factors including age-dependent variation in DRD1 penetrance may facilitate the link between improvements in higher-order working memory and the remission of symptoms in individuals with childhood-diagnosed ADHD. Furthermore, the current findings suggest that DRD1 might contribute minimally to the emergence of symptoms and cognitive difficulties associated with ADHD in childhood, but may act as a modifier gene of these clinical features and outcome during later development for those with ADHD.
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http://dx.doi.org/10.1111/desc.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069210PMC
July 2014

Association between variation in neuropsychological development and trajectory of ADHD severity in early childhood.

Am J Psychiatry 2013 Oct;170(10):1205-11

Objective: This longitudinal study examined if changes in neuropsychological functioning were associated with the trajectory of symptoms related to attention deficit hyperactivity disorder (ADHD) and impairment between preschool and school age.

Method: The sample consisted of 3- and 4-year-old children (N=138) who were identified as being at risk for ADHD based on parent and teacher reports. Neuropsychological functioning was measured annually using the NEPSY at four time points (mean ages, 4.19, 5.36, 6.35, and 7.35 years). ADHD symptoms and impairment were assessed with semiannual parent and teacher reports using the ADHD Rating Scale-IV and the Children's Problems Checklist at 10 time points (mean ages at baseline and final assessment, 4.19 and 8.81 years, respectively). Hierarchical linear modeling was used to assess the trajectories of change in neuropsychological functioning and ADHD severity as well as the association of change in neuropsychological functioning with change in ADHD severity over time.

Results: Baseline neuropsychological functioning was not significantly associated with the slope of change in ADHD severity. However, the magnitude of change in neuropsychological functioning was linearly associated with the trajectory of ADHD symptom severity and impairment, such that individuals with greater neuropsychological growth over time had a greater diminution of ADHD severity and impairment. Family socioeconomic status at baseline was significantly associated with initial ADHD severity and impairment, but not with change over time.

Conclusions: Interventions that enhance neuropsychological functioning at an early age may be beneficial in attenuating long-term ADHD severity and impairment.
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http://dx.doi.org/10.1176/appi.ajp.2012.12101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963820PMC
October 2013

Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults.

Neuropsychopharmacology 2013 Feb 7;38(3):525-32. Epub 2012 Nov 7.

Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD 20892, USA.

The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.
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http://dx.doi.org/10.1038/npp.2012.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547204PMC
February 2013

Perceptual and motor inhibition in adolescents/young adults with childhood-diagnosed ADHD.

Neuropsychology 2010 Jul;24(4):424-34

Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.

Objective: This study examined perceptual and motor inhibition in a longitudinal sample of adolescents/young adults who were diagnosed with ADHD in childhood, and as a function of the relative persistence of ADHD.

Method: Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, sociodemographic background, and gender distribution served as a comparison group. Participants were administered a psychiatric interview and the Stimulus and Response Conflict Tasks (Nassauer & Halperin, 2003).

Results: Participants with childhood ADHD demonstrated slower and less accurate responses to both control and conflict conditions relative to the comparison group, as well as more variable responses in both conditions of the motor inhibition task; there was no specific effect of childhood ADHD on perceptual or motor inhibition. ADHD persisters and partial remitters did not differ in overall accuracy, speed or variability in responding, but relative to partial remitters, persisters demonstrated greater slowing in response to perceptual conflict.

Conclusions: These findings are consistent with theories positing state regulation, but not inhibitory control deficits in the etiology of ADHD, and suggest that improved perceptual inhibition may be associated with better outcome for ADHD.
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http://dx.doi.org/10.1037/a0018752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900812PMC
July 2010

Childhood maltreatment and conduct disorder: independent predictors of adolescent substance use disorders in youth with attention deficit/hyperactivity disorder.

J Clin Child Adolesc Psychol 2008 Oct;37(4):785-93

Graduate Center of the City University of New York, Flushing, NY 11367, USA.

Children with attention deficit/hyperactivity disorder (ADHD) are at heightened risk for maltreatment and later substance use disorders (SUDs). We investigated the relationship of childhood maltreatment and other risk factors to SUDs among adolescents diagnosed with ADHD in childhood. Eighty adolescents diagnosed with ADHD when they were 7 to 11 years old were screened for histories of childhood maltreatment, and SUD diagnoses were formulated in accordance with the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders. Lifetime history of problematic substance use was obtained for each parent at baseline. Childhood maltreatment predicted SUD outcome over and above that accounted for by childhood conduct disorder and problematic parental substance use, two potent predictors of adolescent SUDs.
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http://dx.doi.org/10.1080/15374410802359650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628748PMC
October 2008

The impact of childhood ADHD on dropping out of high school in urban adolescents/ young adults.

J Atten Disord 2009 Sep 29;13(2):127-36. Epub 2008 Aug 29.

Neuropsychology Subprogram, The Graduate Center and Queens College of the City University of New York, NY, USA.

Objective: To examine cognitive and psychosocial factors associated with high school dropout in urban adolescents with and without childhood ADHD.

Method: In a longitudinal study, 49 adolescents/young adults with childhood ADHD and 44 controls who either dropped out or graduated from high school are included. Risk factors examined as potential correlates of dropout were intelligence, reading skills, socioeconomic status, marijuana use, and paternal contact.

Results: Lower IQ, reading ability, socioeconomic status, frequent marijuana use, and limited paternal contact significantly differentiated dropouts from graduates, irrespective of childhood ADHD. Follow-up analyses determined that IQ, marijuana use, and paternal contact independently contribute to the likelihood of dropout.

Conclusion: Selected cognitive and psychosocial factors appear independently associated with the likelihood of high school dropout irrespective of ADHD. Notably, childhood ADHD did not increase this risk, suggesting that previous reports of increased dropout because of ADHD may become negated in urban areas when matched with similar community controls.
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http://dx.doi.org/10.1177/1087054708323040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729363PMC
September 2009

Neuropsychological outcome in adolescents/young adults with childhood ADHD: profiles of persisters, remitters and controls.

J Child Psychol Psychiatry 2008 Sep 28;49(9):958-66. Epub 2008 Jun 28.

Department of Psychology, Queens College, City University of New York, NY 11367, USA.

Background: This study examined neuropsychological functioning in a longitudinal sample of adolescents/young adults with attention deficit/hyperactivity disorder (ADHD) and controls as a function of the persistence of ADHD. We hypothesized that measures of executive processes would parallel adolescent clinical status, with ADHD-persisters, but not remitters, differing significantly from controls. In contrast, persisters and remitters were hypothesized to perform similarly, and different from controls, on tasks requiring less effortful processing.

Methods: Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, and sex distribution served as a comparison group. Participants were administered a psychiatric interview and neuropsychological test battery.

Results: Those with childhood ADHD demonstrated broad neuropsychological deficits relative to controls. When the group with childhood ADHD was subdivided based on adolescent ADHD status, compared to controls, both persisters and remitters showed deficient perceptual sensitivity and response variability, and increased ankle movements recorded by a solid-state actigraph. Only persisters differed from controls on several measures of more effortful executive processes.

Conclusions: Findings provide preliminary support to the hypothesis that ADHD is associated with early-appearing and enduring subcortical dysfunction, while recovery over the course of development is associated with improvements in executive control functions.
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http://dx.doi.org/10.1111/j.1469-7610.2008.01926.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646044PMC
September 2008
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