RESUMEN
Addictions are heritable and unfold dynamically across the lifespan. One prominent neurobiological theory proposes that substance-induced changes in neural circuitry promote the progression of addiction. Genome-wide association studies have begun to characterize the polygenic architecture undergirding addiction liability and revealed that genetic loci associated with risk can be divided into those associated with a general broad-spectrum liability to addiction and those associated with drug-specific addiction risk. In this Perspective, we integrate these genomic findings with our current understanding of the neurobiology of addiction to propose a new Genetically Informed Neurobiology of Addiction (GINA) model.
Asunto(s)
Conducta Adictiva , Trastornos Relacionados con Sustancias , Humanos , Estudio de Asociación del Genoma Completo , Conducta Adictiva/genética , Neurobiología , Trastornos Relacionados con Sustancias/genéticaRESUMEN
Neuroimaging research has uncovered a multitude of neural abnormalities associated with psychopathology, but few prediction-based studies have been conducted during adolescence, and even fewer used neurobiological features that were extracted across multiple neuroimaging modalities. This gap in the literature is critical, as deriving accurate brain-based models of psychopathology is an essential step towards understanding key neural mechanisms and identifying high-risk individuals. As such, we trained adaptive tree-boosting algorithms on multimodal neuroimaging features from the Lifespan Human Connectome Developmental (HCP-D) sample that contained 956 participants between the ages of 8 to 22 years old. Our feature space consisted of 1037 anatomical, 1090 functional, and 192 diffusion MRI features, which were used to derive models that separately predicted internalizing symptoms, externalizing symptoms, and the general psychopathology factor. We found that multimodal models were the most accurate, but all brain-based models of psychopathology yielded out-of-sample predictions that were weakly correlated with actual symptoms (r2 < 0.15). White matter microstructural properties, including orientation dispersion indices and intracellular volume fractions, were the most predictive of general psychopathology, followed by cortical thickness and functional connectivity. Spatially, the most predictive features of general psychopathology were primarily localized within the default mode and dorsal attention networks. These results were mostly consistent across all dimensions of psychopathology, except orientation dispersion indices and the default mode network were not as heavily weighted in the prediction of internalizing and externalizing symptoms. Taken with prior literature, it appears that neurobiological features are an important part of the equation for predicting psychopathology but relying exclusively on neural markers is clearly not sufficient, especially among adolescent samples with subclinical symptoms. Consequently, risk factor models of psychopathology may benefit from incorporating additional sources of information that have also been shown to explain individual differences, such as psychosocial factors, environmental stressors, and genetic vulnerabilities.
RESUMEN
Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study's findings suggest that genetic differences in hippocampal longitudinal axis structure can be detected in individual differences in gray matter volume in population-level research designs.
Asunto(s)
Hipocampo , Imagen por Resonancia Magnética , Adulto , Niño , Humanos , Hipocampo/diagnóstico por imagen , Corteza Cerebral , Sustancia Gris/diagnóstico por imagen , Gemelos/genéticaRESUMEN
BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.
RESUMEN
Studies demonstrate that individuals with diagnoses for Major Depressive Disorder (MDD), Post-traumatic Stress Disorder (PTSD), and Schizophrenia (SCZ) may exhibit smaller hippocampal gray matter relative to otherwise healthy controls, although the effect sizes vary in each disorder. Existing work suggests that hippocampal abnormalities in each disorder may be attributable to genetic liability and/or environmental variables. The following study uses baseline data from the Adolescent Brain and Cognitive Development[Formula: see text] Study (ABCD Study[Formula: see text]) to address three open questions regarding the relationship between genetic risk for each disorder and hippocampal volume reductions: (a) whether polygenic risk scores (PGRS) for MDD, PTSD, and SCZ are related to hippocampal volume; (b) whether PGRS for MDD, PTSD, and SCZ are differentially related to specific hippocampal subregions along the longitudinal axis; and (c) whether the association between PGRS for MDD, PTSD, and SCZ and hippocampal volume is moderated by sex and/or environmental adversity. In short, we did not find associations between PGRS for MDD, PTSD, and SCZ to be significantly related to any hippocampal subregion volumes. Furthermore, neither sex nor enviornmental adversity significantly moderated these associations. Our study provides an important null finding on the relationship genetic risk for MDD, PTSD, and SCZ to measures of hippocampal volume.
Asunto(s)
Trastorno Depresivo Mayor , Esquizofrenia , Trastornos por Estrés Postraumático , Adolescente , Humanos , Niño , Trastorno Depresivo Mayor/genética , Esquizofrenia/genética , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/psicología , Depresión , Hipocampo , Imagen por Resonancia MagnéticaRESUMEN
Alcohol expectancies (AEs) are associated with likelihood of alcohol initiation and subsequent alcohol use disorders. It is unclear whether genetic predisposition to alcohol use and/or related traits contributes to shaping how one expects to feel when drinking alcohol. We used the Adolescent Brain Cognitive Development study to examine associations between genetic propensities (i.e., polygenic risk for problematic alcohol use, depression, risk-taking), sociodemographic factors (i.e., parent income), and the immediate social environment (i.e., peer use and disapproval toward alcohol) and positive and negative AEs in alcohol-naïve children (max analytic N = 5,352). Mixed-effect regression models showed that age, parental education, importance of the child's religious beliefs, adverse childhood experiences, and peer disapproval of alcohol use were associated with positive and/or negative AEs, to varying degrees. Overall, our results suggest several familial and psychosocial predictors of AEs but little evidence of contributions from polygenic liability to problematic alcohol use or related phenotypes.
Asunto(s)
Medio Social , Factores Sociodemográficos , Consumo de Alcohol en Menores , Humanos , Niño , Adolescente , Consumo de Alcohol en Menores/psicología , Predisposición Genética a la Enfermedad , Masculino , Femenino , Factores Socioeconómicos , Experiencias Adversas de la InfanciaRESUMEN
Genetic risk for Late Onset Alzheimer Disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, whether these and other associations are present during childhood remains unclear. Using data from 5556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®), our phenome-wide association study estimating associations between four indices of genetic risk for late-onset AD (i.e., AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (ADPRS-APOE), and an interaction between ADPRS-APOE and APOE genotype) and 1687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps > 0.0002; all pfdr > 0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.
Asunto(s)
Enfermedad de Alzheimer , Niño , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Cognición , Genotipo , Factores de Riesgo , Apolipoproteínas E/genéticaRESUMEN
Alcohol use is a growing global health concern and economic burden. Alcohol involvement (i.e., initiation, use, problematic use, alcohol use disorder) has been reliably associated with broad spectrum grey matter differences in cross-sectional studies. These findings have been largely interpreted as reflecting alcohol-induced atrophy. However, emerging data suggest that brain structure differences also represent pre-existing vulnerability factors for alcohol involvement. Here, we review evidence from human studies with designs (i.e., family-based, genomic, longitudinal) that allow them to assess the plausibility that these correlates reflect predispositional risk factors and/or causal consequences of alcohol involvement. These studies provide convergent evidence that grey matter correlates of alcohol involvement largely reflect predisposing risk factors, with some evidence for potential alcohol-induced atrophy. These conclusions highlight the importance of study designs that can provide causal clues to cross-sectional observations. An integrative model may best account for these data, in which predisposition to alcohol use affects brain development, effects which may then be compounded by the neurotoxic consequences of heavy alcohol use.
Asunto(s)
Corteza Cerebral , Sustancia Gris , Humanos , Sustancia Gris/diagnóstico por imagen , Estudios Transversales , Consumo de Bebidas Alcohólicas , Susceptibilidad a Enfermedades , Etanol , AtrofiaRESUMEN
OBJECTIVES: Purposeful adults may experience greater cognitive resilience because sense of purpose may help buffer against the effects of depressive symptoms and loneliness. We also evaluated whether these associations differed by race. DESIGN: This study uses a wave of self-report data from the SPAN study of psychosocial aging. SETTING: Participants come from a representative sample of older adults in St. Louis. PARTICIPANTS: Participants (N = 595) ages range from 65 to 78 (Mage = 71.46), with 18.3% of participants identifying as Black/African-American. MEASURES: Sense of purpose was assessed with the Life Engagement Test, depressive symptoms with the Beck Depression Inventory-II, loneliness with the UCLA Loneliness Scale, and subjective cognitive decline with the AD-8. RESULTS: Correlational analyses supported predictions that sense of purpose was negatively related to subjective cognitive decline, whereas depressive symptoms and loneliness were positively related (|r|s > .30, ps < .001). For loneliness, but not depression, this association was moderated by sense of purpose (b = -0.43, p < .001). A relatively high sense of purpose attenuated associations between loneliness and subjective cognitive decline. A three-way race × purpose × loneliness interaction (b = -0.25, p = .021) revealed that the buffering effects of sense of purpose on subjective cognitive decline were stronger for Black adults. DISCUSSION: This study provided partial support for the buffering hypothesis, showing that sense of purpose may help mitigate the cognitive decrements associated with loneliness. Future research needs to consider how purpose-promoting programs may support healthy cognitive aging, particularly among Black older adults and those who experience greater social isolation.
Asunto(s)
Disfunción Cognitiva , Salud Mental , Humanos , Anciano , Soledad , Estado de Salud , Aislamiento Social , Disfunción Cognitiva/diagnósticoRESUMEN
Background: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a common single nucleotide polymorphism (SNP) within CD38, rs3796863, is associated with increased social reward.Objective: Examine whether CD38 rs3796863 and Cd38 knockout (KO) are associated with reward-related neural and behavioral phenotypes.Methods: Data from four independent human studies were used to test whether rs3796863 genotype is associated with: (1) intravenous alcohol self-administration (n = 64, 30 females), (2) alcohol-stimulated dopamine (DA) release measured using 11C-raclopride positron emission tomography (n = 22 men), (3) ventral striatum (VS) response to positive feedback measured using a card guessing functional magnetic resonance imaging (fMRI) paradigm (n = 531, 276 females), and (4) resting state functional connectivity (rsfc) of the VS (n = 51, 26 females). In a fifth study, we used a mouse model to examine whether cd38 knockout influences stimulated DA release in the NAc core and dorsal striatum using fast-scanning cyclic voltammetry.Results: Relative to T allele carriers, G homozygotes at rs3796863 within CD38 were characterized by greater alcohol self-administration, alcohol-stimulated dopamine release, VS response to positive feedback, and rsfc between the VS and anterior cingulate cortex. High-frequency stimulation reduced DA release among Cd38 KO mice had reduced dopamine release in the NAc.Conclusion: Converging evidence suggests that CD38 rs3796863 genotype may increase DA-related reward response and alcohol consumption.
Asunto(s)
ADP-Ribosil Ciclasa 1/genética , Etanol/farmacología , Glicoproteínas de Membrana/genética , Racloprida/metabolismo , Recompensa , Estriado Ventral/fisiología , Animales , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Retroalimentación , Femenino , Genotipo , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Noqueados , Núcleo Accumbens/metabolismo , Polimorfismo de Nucleótido Simple/genética , Tomografía de Emisión de Positrones , AutoadministraciónRESUMEN
One generation's experience of childhood maltreatment is associated with that of the next. However, whether this intergenerational transmission is specific to distinct forms of maltreatment and what factors may contribute to its continuity remains unclear. Borderline personality pathology is predicted by childhood maltreatment and characterized by features (e.g., dysregulated emotion, relationship instability, impulsivity, and inconsistent appraisals of others) that may contribute to its propagation. Among 364 older adults and 573 of their adult children (total n = 937), self-reported exposure to distinct forms of childhood maltreatment (i.e., emotional, physical, and sexual abuse, and emotional and physical neglect as assessed by the Childhood Trauma Questionnaire) showed homotypic and heterotypic associations across generations with little evidence that latent factors unique to specific forms of maltreatment show generational continuity. General nonspecific indices of childhood maltreatment showed evidence of intergenerational transmission after accounting for demographic factors and parent socioeconomic status (b = 0.126, p = 9.21 × 10-4). This continuity was partially mediated by parental borderline personality pathology (assessed longitudinally through a variety of measures and sources, indirect effect: b = 0.031, 95% confidence interval [0.003, 0.060]). The intergenerational continuity of childhood maltreatment may largely represent general risk for nonspecific maltreatment that may, in part, be propagated by borderline personality pathology and/or shared risk factors.
Asunto(s)
Adultos Sobrevivientes del Maltrato a los Niños/psicología , Trastorno de Personalidad Limítrofe/psicología , Emociones/fisiología , Personalidad/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
OBJECTIVE: We examined race/gender effects on initial levels and trajectories of self-reported physical and mental health, as well as the moderating role of personality. We hypothesized that health disparities would remain stable or decrease over time, and that at-risk personality traits (e.g., neuroticism) would have a more robust negative impact on health for Black participants. METHOD: Analyses utilized 6 waves of data from a community sample of 1,577 Black and White adults (mean age 60 years), assessed every 6 months for 2.5 years. Using multigroup latent growth curve modeling, we examined initial levels and changes in health among White men, White women, Black men, and Black women. RESULTS: Black participants reported lower initial physical health than Whites. Women's physical health was stable over time, whereas men's declined. There were no disparities in mental health. Higher agreeableness was associated with higher initial levels of physical health only among Black men and White women. All other personality traits were associated with physical and mental health similarly across race and gender. CONCLUSIONS: Race and gender influence health trajectories. Most personality- health associations replicated across race and gender, except for agreeableness with physical health. An intersectional framework considering more than one aspect of social identity is crucial for understanding health disparities. Future studies may benefit from including large, diverse samples of participants and further examining the moderating effects of race and gender on personality associations with a variety of health outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Asunto(s)
Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Disparidades en el Estado de Salud , Personalidad/fisiología , Población Blanca/psicología , Población Blanca/estadística & datos numéricos , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Autoinforme , Distribución por SexoRESUMEN
Genomewide association studies (GWASs) across psychiatric phenotypes have shown that common genetic variants generally confer risk with small effect sizes (odds ratio < 1.1) that additively contribute to polygenic risk. Summary statistics derived from large discovery GWASs can be used to generate polygenic risk scores (PRS) in independent, target data sets to examine correlates of polygenic disorder liability (e.g., does genetic liability to schizophrenia predict cognition?). The intuitive appeal and generalizability of PRS have led to their widespread use and new insights into mechanisms of polygenic liability. However, when currently applied across traits they account for small amounts of variance (<3%), are relatively uninformative for clinical treatment, and, in isolation, provide no insight into molecular mechanisms. Larger GWASs are needed to increase the precision of PRS, and novel approaches integrating various data sources (e.g., multitrait analysis of GWASs) may improve the utility of current PRS.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Individualidad , Trastornos Mentales , Psicología Clínica/métodos , Humanos , Trastornos Mentales/epidemiología , Trastornos Mentales/etiología , Trastornos Mentales/genéticaRESUMEN
Older adults are the largest consumer of cable news, which includes negative and politicized content and may constitute a daily stressor. As older adults are also vulnerable to the negative consequences of stress, we hypothesized that cable news watching could induce a stress reaction and impair cognitive function. We tested exposures to cable news (i.e., Fox News and MSNBC) in a within-subject randomized controlled design in 34 healthy older adults. We also included negative (Public Broadcasting Station) and positive (trier social stress test) controls. Cable news watching had no effect on psychological stress, physiological stress, or cognitive function. This remained true even if the news exposures were discordant with participants' political affiliation. We conclude that brief cable news watching does not induce a physiological or subjective stress response or cognitive impairment among healthy older adults.
Asunto(s)
Envejecimiento/fisiología , Cognición/fisiología , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Televisión , Anciano , Estudios Cruzados , Femenino , Humanos , Masculino , PolíticaRESUMEN
In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.
Asunto(s)
Repetición de Anquirina/genética , Cuerpo Estriado/metabolismo , Obesidad/genética , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Adolescente , Adulto , Alelos , Benperidol/análogos & derivados , Benperidol/farmacocinética , Estudios de Casos y Controles , Cuerpo Estriado/diagnóstico por imagen , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Unión Proteica , Radiofármacos/farmacocinética , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismoRESUMEN
Personality predicts the occurrence of dependent stressful life events (SLE; i.e., events reliant, at least in part, on an individual's behavior). This process, termed stress generation, contributes to psychiatric outcomes, but its role in physical health is unknown. Data were included from 998 participants (aged 55-64) in the St. Louis Personality and Aging Network (SPAN) study. Assessments occurred every 6 months for 18 months. Neuroticism, impulsivity, and agreeableness were measured with the Revised NEO Personality Inventory. Dependent (e.g., divorce) and independent (e.g., family death) SLE occurring within 6 months following baseline were assessed with the List of Threatening Experiences and confirmed by interviews. Health problems occurring within a year after SLE were the outcome. Analyses examined whether neuroticism, impulsivity, and agreeableness indirectly predict the onset of new health problems through exposure to dependent SLE. Each personality trait was associated with dependent, but not independent, SLE. Only dependent SLE predicted new health problems. Each personality trait indirectly predicted the onset of new health problems through dependent SLE. Findings suggest that personality-driven stress generation influences physical health during late mid-life. Addressing personality in interventions may reduce the occurrence of SLE, in turn decreasing health risks.
Asunto(s)
Estado de Salud , Acontecimientos que Cambian la Vida , Personalidad , Estrés Psicológico , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Accumulating evidence suggests a role for stress exposure, particularly during early life, and for variation in genes involved in stress response pathways in neural responsivity to emotional stimuli. Understanding how individual differences in these factors predict differences in emotional responsivity may be important for understanding both normative emotional development and for understanding the mechanisms underlying internalizing disorders, like anxiety and depression, that have often been related to increased amygdala and hippocampus responses to negatively valenced emotional stimuli. The present study examined whether stress exposure and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predict individual differences in amygdala and hippocampus responses to fearful vs. neutral faces in school-age children (7-12 year olds; N = 107). Experience of more stressful and traumatic life events predicted greater left amygdala responses to negative emotional stimuli. Genetic profile scores interacted with sex and pubertal status to predict amygdala and hippocampus responses. Specifically, genetic profile scores were a stronger predictor of amygdala and hippocampus responses among pubertal vs. prepubertal children where they positively predicted responses to fearful faces among pubertal girls and positively predicted responses to neutral faces among pubertal boys. The current results suggest that genetic and environmental stress-related factors may be important in normative individual differences in responsivity to negative emotional stimuli, a potential mechanism underlying internalizing disorders. Further, sex and pubertal development may be key moderators of the effects of stress-system genetic variation on amygdala and hippocampus responsivity, potentially relating to sex differences in stress-related psychopathology.
Asunto(s)
Amígdala del Cerebelo/fisiología , Reconocimiento Facial/fisiología , Miedo/fisiología , Hipocampo/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Estrés Psicológico/fisiopatología , Mapeo Encefálico , Niño , Expresión Facial , Femenino , Humanos , Individualidad , Imagen por Resonancia Magnética , Masculino , Polimorfismo de Nucleótido Simple , Pubertad , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Factores Sexuales , Estrés Psicológico/genética , Proteínas de Unión a Tacrolimus/genéticaRESUMEN
BACKGROUND: Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings highlight the need for further research. Converging evidence suggests that the effects of 5-HTTLPR genotype may be neurodevelopmental in origin, but we are not aware of empirical studies that have investigated whether the 5-HTTLPR genotype × SLE interaction predicts preschool-onset depression (PO-MDD), the earliest validated form of depression. METHODS: Children (n = 234) aged 3-5 were recruited for a longitudinal study designed to examine PO-MDD. In a comprehensive baseline assessment, the child's primary caregivers completed questionnaires and were interviewed about their child's behaviors, psychiatric symptoms, and exposure to SLEs. RESULTS: A 5-HTTLPR × SLEs interaction emerged, such that children homozygous for the short allele were more susceptible to depression in the context of elevated SLE than long allele carriers. In contrast, at low SLE exposure, short allele homozygotes had fewer depressive symptoms. The data were best fit by a plasticity model with a substantial reduction in fit by diathesis-stress models. CONCLUSIONS: Extending studies in adult and adolescent populations, these data suggest that 5-HTTLPR genotype may provide plasticity to environmental influence, for better or worse. Specifically, children homozygous for the short allele were more susceptible to the depressogenic effects of SLEs but benefitted, in the form of reduced depressive symptoms, in the context of relatively benign environmental conditions (i.e. relatively low SLE exposure). These data highlight the importance of examining gene × environment interactions across development, environment, and outcome but should be interpreted cautiously given the small sample size.
Asunto(s)
Depresión/genética , Predisposición Genética a la Enfermedad/genética , Acontecimientos que Cambian la Vida , Polimorfismo de Nucleótido Simple/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Desarrollo Infantil , Preescolar , Depresión/etiología , Depresión/psicología , Femenino , Genotipo , Humanos , Estudios Longitudinales , MasculinoRESUMEN
Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.
Asunto(s)
Estudio de Asociación del Genoma Completo , Trastornos Relacionados con Sustancias , Humanos , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/epidemiología , Predisposición Genética a la Enfermedad , Herencia MultifactorialRESUMEN
BACKGROUND: Studies of prenatal substance exposure often rely on self-report, urine drug screens, and/or analyses of blood or meconium biomarkers. Accuracy of these measures is limited when assessing exposure over many weeks or months of gestation. Nails are increasingly being considered as a matrix from which to assess substance exposure. This systematic review synthesizes data on the validity of detecting alcohol, nicotine, cannabis, and opioid from nail clippings, with an emphasis on prenatal exposure assessment. METHODS: The systematic review was conducted using PRISMA 2020 guidelines. Seven databases were searched with keywords relevant to the four substances of interest. Results were summarized grouping manuscripts by the exposure of interest with focus on accuracy and feasibility. RESULTS: Of 2384 papers initially identified, 35 manuscripts were included in our qualitative synthesis. Only a few studies specifically looked at pregnant individuals or mother-child dyads. Across the four substances, many studies demonstrated a dose-response relationship between exposure and concentration of analytes in nails. Nail assays appear to detect lower level of exposure compared to hair; however, sample insufficiency, especially for multi-substance assays, remains a limitation. CONCLUSIONS: Based on the reviewed studies, nail clippings are an acceptable and potentially preferable matrix for the evaluation of these four prenatal substances when sampling frequency and/or study design necessitates assessment of past exposures over an extended period. Nails have the advantage of infrequent sampling and minimal invasiveness to assess a broad exposure period. Future studies should examine validity of analytes in toenail versus fingernail clippings.