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1.
Hum Mol Genet ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518406

RESUMO

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. While the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. While it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition towards loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study (GWAS) meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with electronic health record data to conduct a PheWAS with. A genetic predisposition towards loneliness was associated with cardiovascular, psychiatric, and metabolic disorders, and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

2.
Methods Mol Biol ; 2018: 233-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31228160

RESUMO

In this chapter we will review both the rationale and experimental design for using Heterogeneous Stock (HS) populations for fine-mapping of complex traits in mice and rats. We define an HS as an outbred population derived from an intercross between two or more inbred strains. HS have been used to perform genome-wide association studies (GWAS) for multiple behavioral, physiological, and gene expression traits. GWAS using HS require four key steps, which we review: selection of an appropriate HS population, phenotyping, genotyping, and statistical analysis. We provide advice on the selection of an HS, comment on key issues related to phenotyping, discuss genotyping methods relevant to these populations, and describe statistical genetic analyses that are applicable to genetic analyses that use HS.

3.
Methods Mol Biol ; 2018: 319-326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31228165

RESUMO

In this chapter, we briefly review the use of rats as a genetic model for the study of behavior. Rats were the first mammalian species used for genetic and biological research. Since the development of the first inbred rat strain in 1909, more than 700 unique inbred and outbred rat lines have been generated. Although rats have been somewhat eclipsed by mice in the last few decades, a renewed appreciation of the advantages of rats for behavioral and other types of research is upon us. We briefly review the pertinent characteristics of the rat and highlight the key advantages of using the rat to examine behavioral phenotypes.

4.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30998058

RESUMO

Risk-taking behavior can result in a range of maladaptive behaviors such as illicit substance use, unsafe driving, and high-risk sexual behavior. Perception of risk and preference for engaging in risky behaviors have been measured using both self-report measures and a range of behavioral tasks designed for the purpose, and these may predict future risk-taking behavior. However, the interrelationships between these measures and the latent constructs underlying them are poorly understood. In the present study, we examined data from over 1,000 men and women who completed measures of risk-related behaviors, including self-reports of perception of risk, propensity to engage in risky behaviors, and incentivized performance on tasks that involve risk. We conducted principal component analyses (PCAs) to understand the underlying latent structure of these measures. A PCA with the full sample revealed 5 distinct components, corresponding to measures of (a) health/ethical risks, (b) discounting of uncertain rewards, (c) risk of personal finances, (d) preferences in recreational hobbies and social interactions that involve risk, and (e) behavior involving risks in interpersonal interactions. Although we found sex differences on several of the measures, the sex-adjusted PCA components were similar to those of the unadjusted full sample PCA. These findings add to a growing literature revealing different components of the broad category of risk perception and risk-taking behaviors. A better understanding of the multidimensionality of risk preference will help lay the foundation for more refined measures, develop better predictors of future risk-taking behavior, and ultimately to study the genetic or other biological basis of risk-taking. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

6.
Behav Processes ; 162: 157-161, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30876880

RESUMO

Delayed reward discounting (DRD) is a behavioral economic measure of impulsivity, reflecting how rapidly a reward loses value based on its temporal distance. In humans, more impulsive DRD is associated with susceptibility to a number of psychiatric diseases (e.g., addiction, ADHD), health outcomes (e.g., obesity), and lifetime outcomes (e.g., educational attainment). Although the determinants of DRD are both genetic and environmental, this review focuses on its genetic basis. Both rodent studies using inbred strains and human twin studies indicate that DRD is moderately heritable, a conclusion that was further supported by a recent human genome-wide association study (GWAS) that used single nucleotide polymorphisms (SNP) to estimate heritability. The GWAS of DRD also identified genetic correlations with psychiatric diagnoses, health outcomes, and measures of cognitive performance. Future research priorities include rodent studies probing putative genetic mechanisms of DRD and human GWASs using larger samples and non-European cohorts. Continuing to characterize genomic influences on DRD has the potential to yield important biological insights with implications for a variety of medically and socially important outcomes.


Assuntos
Desvalorização pelo Atraso , Genômica , Comportamento Impulsivo , Recompensa , Animais , Comportamento Aditivo , Economia Comportamental , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
7.
Sci Rep ; 9(1): 2351, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787409

RESUMO

There are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, "sensation-seeking" is predictive of the initial propensity to take drugs; whereas "novelty-seeking" predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive salience to reward cues can predict the propensity to approach drug cues, and reinstatement or relapse, even after relatively brief periods of drug exposure. The question addressed here is the extent to which these three 'vulnerability factors' are related; that is, predictive of one another. Some relationships have been reported in small samples, but here a large sample of 1,598 outbred male and female heterogeneous stock rats were screened for Pavlovian conditioned approach behavior (to obtain an index of incentive salience attribution; 'sign-tracking'), and subsequently tested for sensation-seeking and novelty-seeking. Despite the large N there were no significant correlations between these traits, in either males or females. There were, however, novel relationships between multiple measures of incentive salience attribution and, based on these findings, we generated a new metric that captures "incentive value". Furthermore, there were sex differences on measures of incentive salience attribution and sensation-seeking behavior that were not previously apparent.

8.
J Neurosci ; 39(13): 2562-2572, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30718321

RESUMO

Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse and attention-deficit/hyperactivity disorder (ADHD). In collaboration with the genetics company 23andMe, we performed 10 genome-wide association studies on measures of impulsive personality traits [the short version of the UPPS-P Impulsive Behavior Scale, and the Barratt Impulsiveness Scale (BIS-11)] and drug experimentation (the number of drug classes an individual had tried in their lifetime) in up to 22,861 male and female adult human research participants of European ancestry. Impulsive personality traits and drug experimentation showed single nucleotide polymorphism heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with UPPS-P Sensation Seeking (p = 8.3 × 10-9, rs139528938) and showed a suggestive association with Drug Experimentation (p = 3.0 × 10-7, rs2163971; r 2 = 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p = 3.8 × 10-8; rs199694726). The role of these genes was supported by single variant, gene- and transcriptome-based analyses. Multiple subscales from both UPPS-P and BIS showed strong genetic correlations (>0.5) with Drug Experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPS-P and BIS subscales were genetically correlated with ADHD (r g = 0.30-0.51), supporting their validity as endophenotypes. Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.SIGNIFICANCE STATEMENT Impulsive personality traits (IPTs) are heritable traits that are governed by frontal-subcortical circuits and are associated with neuropsychiatric disorders, particularly substance use disorders. We have performed genome-wide association studies of IPTs to identify regions and genes that account for this heritable variation. IPTs and drug experimentation were modestly heritable (5-11%). We identified an association between single nucleotide polymorphisms in CADM2 and both sensation seeking and drug experimentation; and between variants in CACNA1I and negative urgency. The role of these genes was supported by single variant, gene- and transcriptome-based analyses. This study provides evidence that impulsivity can be genetically separated into distinct components. We showed that IPT are genetically associated with substance use and ADHD, suggesting impulsivity is an endophenotype contributing to these psychiatric conditions.

9.
Trends Genet ; 35(5): 317-318, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30797598

RESUMO

Compared with other psychiatric disorders of similar heritabilities, the progress of substance use disorders (SUD) genetics has been slow. With the growing availability of large-scale biobanks with extensive phenotypes from electronic health records (EHR) and genotypes across millions of individuals, this platform is the next tool to accelerate SUD genetics research.

10.
Nat Neurosci ; 22(3): 503, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30622366

RESUMO

The author list was in the wrong order in the HTML version of the original article and in the HTML version of the original correction notice. This has been corrected to show the 23andMe Research Team as the fourth author and Abraham A. Palmer as the last author in both places.

11.
J Med Chem ; 62(3): 1609-1625, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30628789

RESUMO

Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.

12.
Nat Commun ; 9(1): 5162, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514929

RESUMO

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of ~200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.

13.
Sci Rep ; 8(1): 18069, 2018 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-30584246

RESUMO

Both emotional and social traits interact with genetic factors to influence smoking behavior. We previously established a socially acquired nicotine intravenous self-administration model where social learning of a nicotine-associated odor cue reversed conditioned flavor aversion and promoted nicotine intake. In this study, we first phenotyped ~800 adolescent heterogeneous stock rats in open field, novel object interaction, social interaction, elevated plus maze, and marble burying behaviors. These rats were then phenotyped on socially acquired nicotine self-administration. We found 243 significant correlations between different behavioral tests. Principal component regression analysis found that ~10-20% of the variance in nicotine-related measures, such as intake during the first or the last three fixed-ratio sessions, the progressive ratio session, and reinstatement behavior, can be explained by variations in behavioral traits. Factors corresponding to social behavior and anxiety were among the strongest predictors of nicotine intake and reinstatement of nicotine-seeking behavior. We also found many sex differences in behavioral measures. These data indicated that the genetic diversity of this population, in combination with social behaviour and anxiety, are significant contributors to the divergent nicotine self-administration behavior and indicated a high probability of discovering sex-specific genetic mechanisms for nicotine intake in future genome-wide association studies.

14.
Am J Psychiatry ; : appiajp201818040369, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30336701

RESUMO

OBJECTIVE:: Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits. METHOD:: This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P). RESULTS:: The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and DSM-IV alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=-0.24) and ADHD (rg=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects. CONCLUSIONS:: AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30265060

RESUMO

Delayed reward discounting (DRD) is a behavioral economic measure of impulsivity that has been consistently associated with addiction. It has also been identified as a promising addiction endophenotype, linking specific sources of genetic variation to individual risk. A challenge in the studies to date is that levels of DRD are often confounded with prior drug use, and previous studies have also had limited genomic scope. The current investigation sought to address these issues by studying DRD in healthy young adults with low levels of substance use (N = 986; 62% female, 100% European ancestry) and investigating genetic variation genome-wide. The genome-wide approach used a prioritized subset design, organizing the tests into theoretically and empirically informed categories and apportioning power accordingly. Three subsets were used: (a) a priori loci implicated by previous studies; (b) high-value addiction (HVA) markers from the recently developed SmokeScreen array; and (c) an atheoretical genome-wide scan. Among a priori loci, a nominally significant association was present between DRD and rs521674 in ADRA2A. No significant HVA loci were detected. One statistically significant genome-wide association was detected (rs13395777, p = 2.8 × 10-8), albeit in an intergenic region of unknown function. These findings are generally not supportive of the previous candidate gene studies and suggest that DRD has a complex genetic architecture that will require considerably larger samples to identify genetic associations more definitively. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

16.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

17.
Nat Neurosci ; 21(7): 1018, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29752479

RESUMO

In the version of this article initially published, the consortium authorship was not presented correctly. The 23andMe Research Team was listed as the last author, rather than the fourth, and a line directing readers to the Supplementary Note for a list of members did appear but was not directly associated with the consortium name. Also, the Supplementary Note description stated that both member names and affiliations were included; in fact, only names are given. Finally, the URL for S-PrediXcan was given in the Methods as https://github.com/hakyimlab/S-PrediXcan; the correct URL is https://github.com/hakyimlab/MetaXcan. The errors have been corrected in the HTML and PDF versions of the article.

18.
Alcohol Clin Exp Res ; 42(5): 869-878, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29532486

RESUMO

BACKGROUND: Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol (EtOH) drinking. This study assessed whether inhibition of GLO1, or genetic overexpression of Glo1, would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control. METHODS: Male C57BL/6J mice were pretreated with either the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether locomotor response to a range of EtOH doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of EtOH doses in FVB/NJ wild-type and transgenic Glo1 overexpressing mice (Experiment 3). Anxiety-like behavior (time spent in the center of the open field) was assessed in all 3 experiments. RESULTS: The EtOH dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low EtOH doses and potentiated locomotor sedation at higher EtOH doses. No drug or genotype differences were seen in anxiety-like behavior after EtOH treatment. CONCLUSIONS: The dose of pBBG used in this study is within the effective range shown previously to reduce EtOH drinking. Glo1 overexpression has been previously shown to increase EtOH drinking. However, neither manipulation altered the dose-response curve for EtOH's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of EtOH. The present data demonstrate that reduced EtOH drinking caused by GLO1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects.

19.
Pharmacol Biochem Behav ; 167: 36-41, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29505808

RESUMO

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.

20.
Dev Psychopathol ; 30(2): 417-435, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28606210

RESUMO

Emerging developmental perspectives suggest that adverse rearing environments promote neurocognitive adaptations that heighten impulsivity and increase vulnerability to risky behavior. Although studies document links between harsh rearing environments and impulsive behavior on substance use, the developmental hypothesis that impulsivity acts as mechanism linking adverse rearing environments to downstream substance use remains to be investigated. The present study investigated the role of impulsivity in linking child abuse and neglect with adult substance use using data from (a) a longitudinal sample of youth (Study 1, N = 9,421) and (b) a cross-sectional sample of adults (Study 2, N = 1,011). In Study 1, the links between child abuse and neglect and young adult smoking and marijuana use were mediated by increases in adolescent impulsivity. In Study 2, indirect links between child abuse and neglect and substance use were evidenced via delayed reward discounting and impulsivity traits. Among impulsivity subcomponents, robust indirect effects connecting childhood experiences to cigarette use emerged for negative urgency. Negative urgency, positive urgency, and sensation seeking mediated the effect of child abuse and neglect on cannabis and alcohol use. Results suggest that child abuse and neglect increases risk for substance use in part, due to effects on impulsivity. Individuals with adverse childhood experiences may benefit from substance use preventive intervention programs that target impulsive behaviors.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Desvalorização pelo Atraso/fisiologia , Comportamento Impulsivo/fisiologia , Uso da Maconha/psicologia , Fumar/psicologia , Adolescente , Adulto , Maus-Tratos Infantis/psicologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Risco , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
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