RESUMEN
Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.
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Interacciones Huésped-Patógeno/fisiología , Esquizofrenia/inmunología , Esquizofrenia/microbiología , Adulto , Animales , Trastorno Bipolar/genética , Trastorno Bipolar/inmunología , Trastorno Bipolar/microbiología , Encéfalo/metabolismo , Femenino , Expresión Génica/genética , Perfilación de la Expresión Génica , Genotipo , Humanos , Masculino , Trastornos Mentales/genética , Trastornos Mentales/inmunología , Trastornos Mentales/microbiología , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Transducción de Señal/fisiología , Toxoplasma/inmunología , Toxoplasma/patogenicidadRESUMEN
The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (Nâ¯=â¯14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (pâ¯=â¯5.0â¯×â¯10-4) and higher plasma cotinine levels (pâ¯=â¯7.0â¯×â¯10-5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (nâ¯=â¯1,263) and with higher DRD2 gene expression in the striatum (pâ¯=â¯0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.
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Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Receptores de Dopamina D2/genética , Recompensa , Fumar/genética , Fumar/psicología , Adolescente , Conducta del Adolescente/fisiología , Conducta del Adolescente/psicología , Anticipación Psicológica/fisiología , Conducta Adictiva/diagnóstico por imagen , Conducta Adictiva/genética , Conducta Adictiva/fisiopatología , Conducta Adictiva/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Cotinina/sangre , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , Fumar/fisiopatologíaRESUMEN
Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.
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Dependencia de Heroína/genética , Polimorfismo Genético , Adulto , Pueblo Asiatico/genética , China/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Dependencia de Heroína/epidemiología , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas Serina-Treonina Quinasas/genética , Factores de Intercambio de Guanina Nucleótido Rho/genéticaRESUMEN
OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16â years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58â 176 never smokers, 37â 428 former smokers and 32â 028 current smokers (total N=127â 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
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Trastornos de Ansiedad/epidemiología , Ansiedad/epidemiología , Depresión/epidemiología , Trastorno Depresivo/epidemiología , Fumar/epidemiología , Estrés Psicológico/epidemiología , Adolescente , Adulto , Anciano , Causalidad , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Receptores Nicotínicos/genética , Fumar/genética , Adulto JovenRESUMEN
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
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Predisposición Genética a la Enfermedad , Familia de Multigenes/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Nicotínicos/genética , Fumar/genética , Adolescente , Edad de Inicio , Cotinina/metabolismo , Femenino , Sitios Genéticos/genética , Humanos , Internacionalidad , Desequilibrio de Ligamiento/genética , Masculino , Proteínas del Tejido Nervioso/genética , Fenotipo , Tabaquismo/genéticaRESUMEN
BACKGROUND: The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by -1.21 (95% CI -2.01, -0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of -0.38 (-0.68, -0.08) kg/m(2) per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing. CONCLUSIONS: Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.
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Presión Sanguínea/genética , Índice de Masa Corporal , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Receptores Nicotínicos/genética , Estudios de Cohortes , Femenino , Finlandia , Estudios de Asociación Genética , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Familia de Multigenes , Fenotipo , Análisis de Componente Principal , Fumar/genética , Tabaquismo/genéticaRESUMEN
CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
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Proteínas del Tejido Nervioso/genética , Receptores Nicotínicos/genética , Fumar , Tabaquismo , Adolescente , Desarrollo del Adolescente/efectos de los fármacos , Adulto , Edad de Inicio , Europa (Continente)/epidemiología , Femenino , Interacción Gen-Ambiente , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Nicotina/farmacología , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Fumar/epidemiología , Fumar/genética , Tabaquismo/epidemiología , Tabaquismo/genética , Tabaquismo/psicologíaRESUMEN
Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These disorders, which are in part volitional, in part inborn, and in part determined by environmental experience, pose the full range of medical, genetic, policy, and moral challenges. Gene discovery is being facilitated by a variety of powerful approaches, but is in its infancy. It is not surprising that the genes discovered so far act in a variety of ways: via altered metabolism of drug (the alcohol and nicotine metabolic gene variants), via altered function of a drug receptor (the nicotinic receptor, which may alter affinity for nicotine but as discussed may also alter circuitry of reward), and via general mechanisms of addiction (genes such as monoamine oxidase A and the serotonin transporter that modulate stress response, emotion, and behavioral control). Addiction medicine today benefits from genetic studies that buttress the case for a neurobiologic origin of addictive behavior, and some general information on familially transmitted propensity that can be used to guide prevention. A few well-validated, specific predictors such as OPRM1, ADH1B, ALDH2, CHRNA5, and CYP26 have been identified and can provide some specific guidance, for example, to understand alcohol-related flushing and upper GI cancer risk (ADH1B and AKLDH2), variation in nicotine metabolism (CYP26), and, potentially, naltrexone treatment response (OPRM1). However, the genetic predictors available are few in number and account for only a small portion of the genetic variance in liability, and have not been integrated into clinical nosology or care.
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Conducta Adictiva/genética , Epistasis Genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Trastornos Relacionados con Sustancias/genética , Adolescente , Adulto , Alcohol Deshidrogenasa/genética , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Alelos , Conducta Adictiva/epidemiología , Catecol O-Metiltransferasa/genética , Niño , Comorbilidad , Endofenotipos , Etanol/metabolismo , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Modelos Genéticos , Monoaminooxidasa/genética , Polimorfismo Genético , Receptor de Serotonina 5-HT1B/genética , Factores de Riesgo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Fumar/genética , Medio Social , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/metabolismo , Estudios en Gemelos como Asunto , Gemelos/genéticaRESUMEN
BACKGROUND: Alcohol has been shown to critically modulate cyclic adenosine-3',5' monophosphate (cAMP) signaling. A number of downstream effectors that respond to the cAMP signals (e.g., protein kinase A, cAMP response element binding protein) have, in turn, been examined in relation to alcohol consumption. These studies did not, however, delineate the point at which the actions of alcohol on the cAMP cascade might translate into differences in drinking behavior. To further understand the role of cAMP synthesis in alcohol drinking and dependence, we investigated a specific adenylyl cyclase isoform, adenylyl cyclase (AC) Type 7, whose activity is selectively enhanced by ethanol. METHODS: We measured alcohol consumption and preference in mice in which one copy of the Adcy7 gene was disrupted (Adcy7(+/-)). To demonstrate relevance of this gene for alcohol dependence in humans, we tested the association of polymorphisms in the ADCY7 gene with alcohol dependence in a sample of 1703 alcohol-dependent individuals and 1347 control subjects. RESULTS: We show that Adcy7(+/-) female mice have higher preference for alcohol than wild-type mice, whereas there is little difference in alcohol consumption or preference between Adcy7(+/-) male mice and wild-type control subjects. In the human sample, we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels. CONCLUSIONS: These findings implicate adenylyl cyclase Type 7 as a critical component of the molecular pathways contributing to alcohol drinking and the development of alcohol dependence.
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Adenilil Ciclasas/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Alcoholismo/metabolismo , Adenilil Ciclasas/genética , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Animales , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Ratones , Ratones Transgénicos , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , ARN Mensajero/metabolismo , Autoinforme , Factores Sexuales , Encuestas y CuestionariosRESUMEN
Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of â¼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Carácter Cuantitativo Heredable , Población Blanca/genética , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Proteínas del Citoesqueleto , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Ratones , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Proteínas/metabolismo , Factores de TranscripciónRESUMEN
BACKGROUND: CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with nongenetic factors. METHODS: Participants included 4762 subjects from a general population-based, prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years. Information on maternal smoking, socioeconomic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiologic model including genetic and nongenetic factors. RESULTS: Several single nucleotide polymorphisms in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, p = 1.1 × 10(-5)) and in TTC12 (rs10502172, p = 9.1 × 10(-6)). CHRNA3-rs1051730[A] was more common among heavy/regular smokers than nonsmokers with similar effect-sizes at age 14 years (odds ratio [95% CI]: 1.27 [1.06-1.52]) and 31 years (1.28 [1.13-1.44]). TTC12-rs10502172[G] was more common among smokers than nonsmokers with stronger association at 14 years (1.33 [1.11-1.60]) than 31 years (1.14 [1.02-1.28]). In adolescence, carriers of three-four risk alleles at either CHRNA3-rs1051730 or TTC12-rs10502172 had almost threefold odds of smoking regularly than subjects with no risk alleles. TTC12-rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3-rs1051730 on smoking in adulthood was direct. CONCLUSIONS: TTC12-ANKK1-DRD2s seemed to influence smoking behavior mainly in adolescence, and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.
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Predisposición Genética a la Enfermedad , Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Receptores de Dopamina D2/genética , Receptores Nicotínicos/genética , Fumar/genética , Adolescente , Cromosomas Humanos Par 11/genética , Planificación en Salud Comunitaria , Femenino , Finlandia , Frecuencia de los Genes , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Estadísticas no ParamétricasRESUMEN
The Revised Psychopathy Checklist (PCL-R) has shown a moderate association with violence. The efficacy of PCL-R in varying monoamine oxidase A (MAOA) genotypes is, however, unexamined. The aim of this study was to investigate the effect of PCL-R and psychopathy on the risk for violent reconvictions among 167 MAOA genotyped alcoholic offenders. Violent reconvictions and PCL-R scores among violent offenders were assessed after a 7-year non-incarcerated follow-up. Regression analysis was used to evaluate the alcohol exposure and age-adjusted effect of PCL-R score and psychopathy on the risk for reconvictions among differing MAOA genotypes. Results suggest that the PCL-R total score predicts impulsive reconvictions among high-activity MAOA offenders (6.8% risk increase for every one-point increase in PCL-R total score, P = 0.015), but not among low-activity MAOA offenders, whereas antisocial behavior and attitudes predicted reconvictions in both genotypes (17% risk increase among high-activity MAOA offenders and 12.8% increase among low-activity MAOA offenders for every one-point increase in factor 2 score). Both narcissistic self-image with related interpersonal style (factor 1 score) and psychopathy (PCL-R ≥ 30) failed to predict future violence. Results suggest that the efficacy of PCL-R is altered by MAOA genotype, alcohol exposure, and age, which seems important to note when PCL-R is used for risk assessments that will have legal or costly preventive work consequences.
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Trastorno de Personalidad Antisocial/genética , Trastorno de Personalidad Antisocial/psicología , Monoaminooxidasa/genética , Psicopatología , Violencia/psicología , Adulto , Alcoholismo/complicaciones , Alcoholismo/psicología , Lista de Verificación , Finlandia , Genotipo , Humanos , Estudios Longitudinales , Masculino , Polimorfismo Genético/genética , Valor Predictivo de las Pruebas , Escalas de Valoración Psiquiátrica , Estudios Retrospectivos , Adulto JovenRESUMEN
Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n=4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (P(adj) =0.0067; odds ratio=1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.
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Alcoholismo/genética , Alelos , Predisposición Genética a la Enfermedad/genética , Polimorfismo Genético/genética , Receptores de Glucocorticoides/genética , Adolescente , Edad de Inicio , Consumo de Bebidas Alcohólicas/genética , Intoxicación Alcohólica/genética , Estudios de Cohortes , Femenino , Finlandia , Pruebas Genéticas , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Factores SexualesRESUMEN
The XVII World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics (ISPG) took place in San Diego, California from 4 to 8 November 2009. Approximately 550 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illness, including schizophrenia, mood disorders, substance abuse, autism, and attention deficit disorder. Recent advances in the field were discussed, including the genome-wide association studies results, copy number variation (CNV) in the genome, genomic imaging, and large multicenter collaborations. The following report, written by junior travel awardees who were assigned sessions as rapporteurs represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2009 World Congress of Psychiatric Genetics.
Asunto(s)
Trastornos Mentales/genética , Biología Molecular/tendencias , Estudio de Asociación del Genoma Completo , Genómica/tendencias , HumanosRESUMEN
BACKGROUND: A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency. METHODS: Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both. We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes. RESULTS: Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA-H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L). CONCLUSION: Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA.
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Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/enzimología , Alcoholismo/psicología , Maltrato a los Niños/psicología , Criminales/psicología , Conducta Impulsiva/psicología , Monoaminooxidasa/fisiología , Violencia/psicología , Adulto , Factores de Edad , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/genética , Niño , Estudios de Seguimiento , Humanos , Conducta Impulsiva/enzimología , Masculino , Monoaminooxidasa/genética , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. METHOD: The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. RESULTS: African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. CONCLUSIONS: These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.
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Negro o Afroamericano/genética , Maltrato a los Niños/estadística & datos numéricos , Trastornos Relacionados con Sustancias/genética , Población Negra/genética , Niño , Maltrato a los Niños/psicología , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genética de Población , Genotipo , Disparidades en Atención de Salud/estadística & datos numéricos , Humanos , Acontecimientos que Cambian la Vida , Masculino , Persona de Mediana Edad , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Factores Socioeconómicos , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD. A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD+ASPD) and moderates alpha power. Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD+ASPD (P=.004). In the Bethesda sample, the same allele predicted lower alpha power (P=7.37e(-5)). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P=.03). One haplotype in the haplotype block at the 3' region of the gene that included rs3782025 was associated with AUD+ASPD in the Finns (P=.02) and with reduced alpha power in the Bethesda population (P=.00009). Another haplotype in this block was associated with alpha power among PI (P=.03). No associations were found for HTR3A. Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPD. 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics.
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Alcoholismo/genética , Alcoholismo/psicología , Ritmo alfa , Trastorno de Personalidad Antisocial/genética , Trastorno de Personalidad Antisocial/psicología , Receptores de Serotonina/genética , Adulto , Negro o Afroamericano , Alcoholismo/complicaciones , Alelos , Trastorno de Personalidad Antisocial/complicaciones , Estudios de Casos y Controles , Electroencefalografía , Femenino , Finlandia/epidemiología , Frecuencia de los Genes , Haplotipos , Humanos , Indígenas Norteamericanos , Masculino , Trastornos Mentales/genética , Trastornos Mentales/psicología , Fenotipo , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Receptores de Serotonina 5-HT3 , Factores de Riesgo , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: Environmental factors appear to interact with a functional polymorphism (MAOA-LPR) in the promoter region of the monoamine oxidase A gene (MAOA) in determining some forms of antisocial behavior. However, how MAOA-LPR modulates the effects of other factors such as alcohol consumption related to antisocial behavior is not completely understood. METHODS: This study examines the conjunct effect of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. Recidivism in severe impulsive violent behavior was assessed after 7 to 15 years in a sample of 174 Finnish alcoholic offenders, the majority of whom exhibited antisocial or borderline personality disorder or both, and featured impulsive temperament traits. RESULTS: The risk for committing new acts of violence increased by 2.3% for each kilogram of increase in yearly mean alcohol consumption (p = 0.004) and decreased by 7.3% for every year among offenders carrying the high activity MAOA genotype. In contrast, alcohol consumption and aging failed to affect violent behavior in the low activity MAOA genotyped offenders. MAOA-LPR showed no main effect on the risk for recidivistic violence. CONCLUSIONS: Violent offenders carrying the high activity MAOA genotype differ in several ways from carriers with the low activity MAOA risk allele previously associated with antisocial behavior. Finnish high activity MAOA genotyped risk alcoholics exhibiting antisocial behavior, high alcohol consumption, and abnormal alcohol-related impulsive and uncontrolled violence might represent an etiologically distinct alcohol dependence subtype.
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Agresión/efectos de los fármacos , Envejecimiento/psicología , Consumo de Bebidas Alcohólicas/psicología , Conducta Impulsiva/genética , Monoaminooxidasa/genética , Violencia , Adulto , Consumo de Bebidas Alcohólicas/genética , Estudios de Seguimiento , Humanos , Conducta Impulsiva/inducido químicamente , Masculino , Polimorfismo Genético , Adulto JovenRESUMEN
BACKGROUND: Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. METHODS: Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. RESULTS: Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. CONCLUSIONS: Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.
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Amidohidrolasas/genética , Ansiedad/genética , Encéfalo/fisiología , Variación Genética/genética , Recompensa , Transducción de Señal , Adulto , Análisis de Varianza , Encéfalo/anatomía & histología , Encéfalo/irrigación sanguínea , Mapeo Encefálico , Moduladores de Receptores de Cannabinoides/genética , Endocannabinoides , Femenino , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Escalas de Valoración Psiquiátrica , Análisis de Regresión , Transducción de Señal/genéticaRESUMEN
The resting EEG is a dynamic index of cortical activation, cognitive function and consciousness and is therefore an intermediate phenotype for many behaviors in which arousal is implicated such as anxiety and alcoholism. We performed a dense whole genome linkage scan using 3878 unlinked SNPs in a large pedigree derived from a population isolate sample of 328 Plains American Indians. Alpha (8-13 Hz), theta (4-8 Hz) and beta (13-30 Hz) EEG power was heritable (0.58-0.27) and stable over a 2 year period (r = 0.82-0.53). Genetic correlations between frequency bands were high (0.75). Linkage peaks for EEG power in all three frequency bands converged on chromosome 5q13-14 with genome-wide significant LOD scores of 3.5 (empirical p<0.0001) for alpha and beta power. A logical candidate gene, corticotropin releasing hormone-binding protein (CRH-BP), was located at the apex of these convergent linkage peaks. CRH-BP was significantly associated with alpha power in the Plains Indians and also in a replication sample of 188 Caucasians. Moreover, the same SNPs and haplotypes, located within the CRH-BP haplotype block, were also associated with anxiety disorders in the Plains Indians and alcohol use disorders in the Caucasians. CRH-BP modulates CRH which influences cortical and hippocampal EEG activity and is the primary mediator of the neuroendocrine stress response. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction.