Moderator Effects of Working Memory on Symptom Stability in Attention-Deficit/Hyperactivity Disorder by Dopamine D1 and D2 Receptor Polymorphisms During Development

Background: Developmental changes in dopaminergic pathways in the prefrontal cortex (PFC) that are important for working memory have been hypothesized to play a central role in the trajectory of attention-deficit/hyperactivity disorder (ADHD), but not the initial onset of the disorder. This dissertation research examines whether dopamine receptor D1 (DRD1) and dopamine receptor D2 (DRD2) gene polymorphisms moderate the association between improvements in working memory and declines in attention problems in ADHD from childhood to adolescence/young adulthood. Methods: Participants were 76 racially/ethnically diverse youth diagnosed with ADHD in childhood and followed prospectively for almost 10 years. Stability of ADHD symptomatology was measured as a quantitative trait using the Attention Problems scale from the Child Behavior Checklist collected both in childhood and adolescence/young adulthood. Digit Span Forward and Digit Span Backward were administered at both time points to assess working memory maintenance and manipulation, respectively. Genotype and age were moderator variables. Results: DRD1 and DRD2 polymorphisms were associated with the stability of attention problems in adolescence/young adulthood, but not childhood. DRD1 polymorphisms, but not DRD2, significantly moderated the association between working memory and attention problems, with the strongest effects evidenced during adolescence/young adulthood. Notably, DRD1 moderation of working memory on attention problems was specific to manipulation performance. Conclusions: Attention problems decreased over the course of almost 10 years if manipulation concomitantly improved during this period of development in a subgroup of individuals with childhood-diagnosed ADHD depending on their genetic makeup

Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

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 × 10−8. 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

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

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.Peer reviewe

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

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, 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.Peer reviewe

The genetics of endophenotypes of neurofunction to understand schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project

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 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

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

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

Severe deprivation in early childhood leads to permanent growth stunting: Longitudinal analysis of height trajectories from childhood-to-adulthood

Background Childhood institutional deprivation is associated with growth stunting in childhood but long-term effects in adulthood remain uncertain. Objective To examine the impact of global institutional deprivation experienced in early childhood on subsequent growth with a special focus on final adult height and puberty timing. Participants &amp; setting The study was originally set in the UK, though some adoptive families lived abroad by the time of the adult follow up. 165 individuals adopted by UK families before 43 months of age from Romanian orphanages after the fall of the Ceaușescu regime in the early 1990's were compared to 51 non-deprived UK adoptees, adopted before the age of 6 months. Methods The English and Romanian Adoptees (ERA) study is a 20-year longitudinal natural experiment on the effects of institutional deprivation on development. Key growth milestones were extracted from growth curve modelling of height data collected at ages 4, 6, 11, 15 and 23 years using a Bayesian approach to fit the JPA2 model. Results Deprivation effects on height were present at the take-off point of accelerating adolescent growth and persisted into adulthood – the largest effects being for individuals who experienced over six months of deprivation. Deprivation was associated with earlier take-off and achievement of peak height velocity of adolescent growth acceleration – an effect driven largely by females' data and correlated with parent ratings of pubertal development. Conclusions Early deprivation appears to reset tempo of growth early in development leading to permanent growth stunting in adulthood and accelerated onset of puberty, specifically in females