Search

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.

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.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P

BACKGROUND:Childhood maltreatment is one of the most potent predictors of future psychopathology, including internalizing disorders. It remains unclear whether heightened amygdala reactivity to threat and elevated stress exposure may be implicated in the pathogenesis and maintenance of internalizing disorders among individuals with a history of childhood maltreatment. METHODS:Using data from a sample of 1,144 young adults, we investigated the contribution of baseline threat-related amygdala reactivity and prospective major stressful life events to internalizing symptoms severity 1 year later (on average) in individuals with a history of maltreatment (n = 100) and propensity score matched nonmaltreated peers (n = 96). RESULTS:Even after stringently matching for several potentially confounding variables - including baseline internalizing symptoms, socioeconomic status and IQ - childhood maltreatment status predicted increased amygdala reactivity at baseline, elevated post-baseline exposure to major stressful life events and internalizing symptoms at follow-up. We also showed, for the first time, that amygdala reactivity at baseline and also post-baseline exposure to major stressful life events mediated the association between a history of maltreatment and future internalizing symptoms. CONCLUSIONS:These findings provide support for the view that maltreatment is a potent developmental insult leading to long-lasting neurocognitive recalibrations of the threat processing system. It is possible that such alterations, over time, may impact mental health functioning by compromising the ability to effectively negotiate everyday challenges (stress susceptibility). These alterations were not, however, found to sensitize an individual to the impact of major stressful life events. The results of this study also lend compelling support to the view that increased psychiatric risk, in the context of childhood maltreatment, follows from an increased propensity to experience major stressful life events (stress generation).

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'.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. 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.

We have previously reported that threat-related amygdala activity measured during a baseline fMRI scan predicts the experience of depression and anxiety associated with stressful life events years later. Here, we examine whether two broad measures of childhood environmental enrichment, namely parental educational achievement and subjective parental socioeconomic status, buffer against the effects of amygdala activity on future vulnerability to stress. Analyses of data available from 579 young adults revealed that maternal, but not paternal, educational achievement moderates the association between amygdala activity, recent life stress, and changes in mood and anxiety symptoms, even when controlling for participants' current subjective socioeconomic status. Specifically, only participants reporting lower maternal educational achievement exhibited our previously observed interaction between amygdala activity and future life stress predicting increases in depression and anxiety. These results suggest that higher maternal educational achievement may help buffer stress sensitivity associated with heightened threat-related amygdala activity.

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.

Recent neuroimaging studies have suggested divergent relationships between antisocial behavior (AB) and callous-unemotional (CU) traits and amygdala reactivity to fearful and angry facial expressions in adolescents. However, little work has examined if these findings extend to dimensional measures of behavior in ethnically diverse, non-clinical samples, or if participant sex, ethnicity, pubertal stage, and age moderate associations. We examined links between amygdala reactivity and dimensions of AB and CU traits in 220 Hispanic and non-Hispanic Caucasian adolescents (age 11-15; 49.5% female; 38.2% Hispanic), half of whom had a family history for depression and thus were at relatively elevated risk for late starting, emotionally dysregulated AB. We found that AB was significantly related to increased right amygdala reactivity to angry facial expressions independent of sex, ethnicity, pubertal stage, age, and familial risk status for depression. CU traits were not related to fear- or anger-related amygdala reactivity. The present study further demonstrates that AB is related to increased amygdala reactivity to interpersonal threat cues in adolescents, and that this relationship generalizes across sex, ethnicity, pubertal stage, age, and familial risk status for depression.

Increased levels of peripheral inflammatory markers, including C-Reactive Protein (CRP), are associated with increased risk for depression, anxiety, and suicidality. The brain mechanisms that may underlie the association between peripheral inflammation and internalizing problems remain to be determined. The present study examines associations between peripheral CRP concentrations and threat-related amygdala activity, a neural biomarker of depression and anxiety risk, in a sample of 172 young adult undergraduate students. Participants underwent functional MRI scanning while performing an emotional face matching task to obtain a measure of threat-related amygdala activity to angry and fearful faces; CRP concentrations were assayed from dried blood spots. Results indicated a significant interaction between CRP and sex: in men, but not women, higher CRP was associated with higher threat-related amygdala activity. These results add to the literature finding associations between systemic levels of inflammation and brain function and suggest that threat-related amygdala activity may serve as a potential pathway through which heightened chronic inflammation may increase risk for mood and anxiety problems.

BackgroundWilliams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior.MethodsThrough an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students.ResultsThe GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men.ConclusionsA common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.

Personality traits such as conscientiousness as self-reported by individuals can help predict a range of outcomes, from job performance to longevity. Asking others to rate the personality of their acquaintances often provides even better predictive power than using self-report. Here, we examine whether peer-reported personality can provide a better link between brain function, namely threat-related amygdala activity, and future health-related behavior, namely problem drinking, than self-reported personality. Using data from a sample of 377 young adult university students who were rated on five personality traits by peers, we find that higher threat-related amygdala activity to fearful facial expressions is associated with higher peer-reported, but not self-reported, conscientiousness. Moreover, higher peer-reported, but not self-reported, conscientiousness predicts lower future problem drinking more than one year later, an effect specific to men. Remarkably, relatively higher amygdala activity has an indirect effect on future drinking behavior in men, linked by peer-reported conscientiousness to lower future problem drinking. Our results provide initial evidence that the perceived conscientiousness of an individual by their peers uniquely reflects variability in a core neural mechanism supporting threat responsiveness. These novel patterns further suggest that incorporating peer-reported measures of personality into individual differences research can reveal novel predictive pathways of risk and protection for problem behaviors.

Calculating math problems from memory may seem unrelated to everyday processing of emotions, but they have more in common than one might think. Prior research highlights the importance of the dorsolateral prefrontal cortex (dlPFC) in executive control, intentional emotion regulation, and experience of dysfunctional mood and anxiety. While it has been hypothesized that emotion regulation may be related to 'cold' (ie. not emotion-related) executive control, this assertion has not been tested. We address this gap by providing evidence that greater dlPFC activity during 'cold' executive control is associated with increased use of cognitive reappraisal to regulate emotions in everyday life. We then demonstrate that in the presence of increased life stress, increased dlPFC activity is associated with lower mood and anxiety symptoms and clinical diagnoses. Collectively, our results encourage ongoing efforts to understand prefrontal executive control as a possible intervention target for improving emotion regulation in mood and anxiety disorders.

Common functional polymorphisms in the gene encoding interleukin-18 (IL18), a cytokine belonging to the IL-1 superfamily that can induce synthesis of several other cytokines, have been associated with major depressive episodes following the experience of stressful life events. The neural mechanisms underlying these associations remain unexamined. Here we use an imaging genetics strategy to examine the effects of risk-related IL18 haplotypes comprising rs187238 and rs1946518 on threat-related amygdala reactivity and, through an indirect effect, stress-related symptoms of depression and anxiety in 448 non-Hispanic Caucasian university students. Analyses indicated that women but not men possessing an IL18 haplotype comprising both risk-related alleles evidenced increased threat-related left centromedial amygdala reactivity relative to other haplotype groups. Moreover, in women only, increased threat-related left centromedial amygdala reactivity predicted increased symptoms of depression and anxiety in individuals also reporting higher levels of life stress. Path analyses revealed a significant indirect effect of IL18 risk haplotype on symptoms of depression and anxiety through increased threat-related amygdala reactivity. These results suggest that a common functional IL18 haplotype associated with heightened proinflammatory responses confers susceptibility to stress-related depression and anxiety through effects on threat-related amygdala function, a risk pathway specific to women. If replicated, these patterns can inform the search for personalized interventions targeting neurobiological pathways of risk associated with inflammation.

Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.

ObjectiveAlthough heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder.MethodAt baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events.ResultsThreat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms.ConclusionsThese results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events.

We all experience a host of common life stressors such as the death of a family member, medical illness, and financial uncertainty. While most of us are resilient to such stressors, continuing to function normally, for a subset of individuals, experiencing these stressors increases the likelihood of developing treatment-resistant, chronic psychological problems, including depression and anxiety. It is thus paramount to identify predictive markers of risk, particularly those reflecting fundamental biological processes that can be targets for intervention and prevention. Using data from a longitudinal study of 340 healthy young adults, we demonstrate that individual differences in threat-related amygdala reactivity predict psychological vulnerability to life stress occurring as much as 1 to 4 years later. These results highlight a readily assayed biomarker, threat-related amygdala reactivity, which predicts psychological vulnerability to commonly experienced stressors and represents a discrete target for intervention and prevention.