RESUMO
Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno da Conduta , Transtornos Relacionados ao Uso de Substâncias , Humanos , Adolescente , Feminino , Criança , Masculino , Estudo de Associação Genômica Ampla , México , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/genética , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/complicaçõesRESUMO
There is a possible accelerated biological aging in patients with substance use disorders (SUD). The evaluation of epigenetic clocks, which are accurate estimators of biological aging based on DNA methylation changes, has been limited to blood tissue in patients with SUD. Consequently, the impact of biological aging in the brain of individuals with SUD remains unknown. In this study, we evaluated multiple epigenetic clocks (DNAmAge, DNAmAgeHannum, DNAmAgeSkinBlood, DNAmPhenoAge, DNAmGrimAge, and DNAmTL) in individuals with SUD (n = 42), including alcohol (n = 10), opioid (n = 19), and stimulant use disorder (n = 13), and controls (n = 10) in postmortem brain (prefrontal cortex) and blood tissue obtained from the same individuals. We found a higher DNAmPhenoAge (ß = 0.191, p-value = 0.0104) and a nominally lower DNAmTL (ß = -0.149, p-value = 0.0603) in blood from individuals with SUD compared to controls. SUD subgroup analysis showed a nominally lower brain DNAmTL in subjects with alcohol use disorder, compared to stimulant use disorder and controls (ß = 0.0150, p-value = 0.087). Cross-tissue analyzes indicated a lower blood DNAmTL and a higher blood DNAmAge compared to their respective brain values in the SUD group. This study highlights the relevance of tissue specificity in biological aging studies and suggests that peripheral measures of epigenetic clocks in SUD may depend on the specific type of drug used.
Assuntos
Alcoolismo , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtornos Relacionados ao Uso de Substâncias/genética , Metilação de DNA/genética , Epigenômica , Envelhecimento/genética , Encéfalo , Epigênese Genética/genéticaRESUMO
OBJECTIVE: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms. METHODS: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases. RESULTS: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use. CONCLUSIONS: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.
Assuntos
Amidoidrolases , Catecol O-Metiltransferase , Esquizofrenia , Transtornos Relacionados ao Uso de Substâncias , Amidoidrolases/genética , Catecol O-Metiltransferase/genética , Frequência do Gene/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Prevenção do Suicídio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/patologia , Transcriptoma , Adulto JovemRESUMO
Background: Several records of high prevalence of HBV have been made in northern Brazil. Among risk groups for viral infection, people who use illicit drugs (PWUDs) stand out, especially if they inject drugs and engage in risky sexual behavior. Objectives: In this study, the prevalence, genotype distribution and factors associated with hepatitis B virus (HBV) exposure in PWUDs were estimated. Methods: This cross-sectional study used snowball sampling from nine different sites. Socio-demographic, economic, drug use and health-related information were collected of 308 PWUDs from nine municipalities in the state of Amapá, northern Brazil. Blood samples were tested for the presence of HBV using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Logistic regressions were run to identify factors independently associated with HBV exposure. Results: In total, seventy (22.7%) PWUDs were exposed to HBV, and 12 (3.9%) had DNA HBV. Genotypes A (58.4%), D (33.3%) and F (8.3%) were identified. Age ≥35 years, use of injectable drug, daily use of drugs, use of drugs over 12 years, unprotected sex, exchange sex for money/drugs, and >12 sexual partners in the last 12 months were associated with exposure to HBV. Conclusions: This study identified important information on the epidemiological scenario of HBV infection in PWUDs, highlighting the high prevalence of HBV exposure and the urgent need for measures for control and prevention, especially vaccination against this hepatotropic virus.
Assuntos
Hepatite B , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Adulto , Brasil/epidemiologia , Estudos Transversais , Genótipo , Hepatite B/epidemiologia , Hepatite B/genética , Humanos , Prevalência , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genéticaRESUMO
Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.
Assuntos
Perfilação da Expressão Gênica , Transtornos do Humor , Córtex Pré-Frontal/metabolismo , Transtornos Relacionados ao Uso de Substâncias , Suicídio Consumado , Adolescente , Adulto , Alcoolismo/epidemiologia , Alcoolismo/genética , Alcoolismo/metabolismo , Autopsia , Causas de Morte , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Diagnóstico Duplo (Psiquiatria) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Transtornos do Humor/metabolismo , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Suicídio Consumado/estatística & dados numéricos , Adulto JovemRESUMO
BACKGROUND: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). METHODS: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. RESULTS: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. CONCLUSIONS: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.
Assuntos
Transtorno Bipolar/epidemiologia , Transtornos Mentais/epidemiologia , Esquizofrenia/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Transtorno Bipolar/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Diagnóstico Duplo (Psiquiatria) , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos Mentais/genética , México , Pessoa de Meia-Idade , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto JovemRESUMO
Background Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Esquizofrenia/epidemiologia , Transtorno Bipolar/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Mentais/epidemiologia , Esquizofrenia/genética , Transtorno Bipolar/genética , Diagnóstico Duplo (Psiquiatria) , Transtornos Relacionados ao Uso de Substâncias/genética , Predisposição Genética para Doença , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/epidemiologia , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , MéxicoRESUMO
Twin research in Brazil twin has expanded enormously in recent years, engaging the interests and efforts of many investigators, students and twins. Descriptions and brief summaries of this work and talks given by investigators at local conferences are presented, based on my four-city lecture tour. This is followed by summaries of twin research on infants' viewing of social scenes, religiosity and substance abuse, Down syndrome, and chronic periodontitis. This article concludes with twin-related news and information of general interest, including identical twin property designers, twins with cerebral palsy, twins affected with the Zika virus, a pair of twin writers, twins in sports, and a set of quadruplets from my childhood neighborhood in Riverdale, New York.
Assuntos
Estudos em Gêmeos como Assunto , Brasil/epidemiologia , Periodontite Crônica/epidemiologia , Periodontite Crônica/genética , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Humanos , Lactente , Masculino , Paralisia/epidemiologia , Paralisia/genética , Religião , Esportes , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/genéticaRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (Pcorr = 0.009 and Pcorr = 0.018, respectively) and for rs11568817 with nicotine dependence (Pcorr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorr = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.