RESUMEN
The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for â¼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.
Asunto(s)
Esquizofrenia/genética , Trastornos por Estrés Postraumático/genética , Adulto , Negro o Afroamericano/genética , Trastorno Bipolar/genética , Estudios de Casos y Controles , Trastorno Depresivo Mayor/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Caracteres Sexuales , Factores Sexuales , Población Blanca/genéticaRESUMEN
Traumatic life experiences are associated with alcohol use problems, an association that is likely to be moderated by genetic predisposition. To understand these interactions, we conducted a gene-by-environment genome-wide interaction study (GEWIS) of alcohol use problems in two independent samples, the Army STARRS (STARRS, N=16 361) and the Yale-Penn (N=8084) cohorts. Because the two cohorts were assessed using different instruments, we derived separate dimensional alcohol misuse scales and applied a proxy-phenotype study design. In African-American subjects, we identified an interaction of PRKG1 rs1729578 with trauma exposure in the STARRS cohort and replicated its interaction with trauma exposure in the Yale-Penn cohort (discovery-replication meta-analysis: z=5.64, P=1.69 × 10-8). PRKG1 encodes cyclic GMP-dependent protein kinase 1, which is involved in learning, memory and circadian rhythm regulation. Considering the loci identified in stage-1 that showed same effect directions in stage-2, the gene ontology (GO) enrichment analysis showed several significant results, including calcium-activated potassium channels (GO:0016286; P=2.30 × 10-5), cognition (GO:0050890; P=1.90 × 10-6), locomotion (GO:0040011; P=6.70 × 10-5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10-5). To our knowledge, this is the largest GEWIS performed in psychiatric genetics, and the first GEWIS examining risk for alcohol misuse. Our results add to a growing body of literature highlighting the dynamic impact of experience on individual genetic risk.
Asunto(s)
Alcoholismo/genética , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Interacción Gen-Ambiente , Acontecimientos que Cambian la Vida , Mutación/genética , Adolescente , Adulto , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.
Asunto(s)
Cromosomas Humanos Par 10/genética , Abuso de Marihuana/genética , Adulto , Negro o Afroamericano/genética , Alelos , Cannabis , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética , Adulto JovenRESUMEN
Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.
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ADN (Citosina-5-)-Metiltransferasas/genética , Tabaquismo/genética , Adulto , Negro o Afroamericano/genética , Anciano , Alelos , Población Negra/genética , ADN (Citosina-5-)-Metiltransferasas/fisiología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Fumar/genética , Población Blanca/genética , ADN Metiltransferasa 3BRESUMEN
OBJECTIVE: To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS: High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS: The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10-5 ; GO:1990454, P = 4.49 × 10-6 ; GO:0030315, P = 2.07 × 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10-4 ). CONCLUSIONS: These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure.
Asunto(s)
Alcoholismo , Trastorno Bipolar , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Personal Militar/estadística & datos numéricos , Trauma Psicológico , Adolescente , Adulto , Alcoholismo/epidemiología , Alcoholismo/etiología , Alcoholismo/genética , Trastorno Bipolar/epidemiología , Trastorno Bipolar/etiología , Trastorno Bipolar/genética , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/etiología , Trastorno Depresivo Mayor/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Masculino , Trauma Psicológico/complicaciones , Trauma Psicológico/epidemiología , Trauma Psicológico/genética , Esquizofrenia/epidemiología , Esquizofrenia/etiología , Esquizofrenia/genética , Tabaquismo/epidemiología , Tabaquismo/etiología , Tabaquismo/genética , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the µ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n=383), we identified a genome-wide significant association between therapeutic methadone dose (mean=68.0 mg, s.d.=30.1 mg) and rs73568641 (P=2.8 × 10-8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg day-1 of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8 mg, s.d.=33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n=241, P=3.9 × 10-2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n=1410, genetic score P=1.3 × 10-3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.
Asunto(s)
Analgésicos Opioides/farmacología , Trastornos Relacionados con Opioides/genética , Dolor/genética , Adulto , Negro o Afroamericano/genética , Alelos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Metadona/uso terapéutico , Persona de Mediana Edad , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Polimorfismo de Nucleótido Simple/genética , Receptores Opioides mu/genética , Estados Unidos , Población Blanca/genéticaRESUMEN
Nicotine withdrawal symptoms contribute to relapse in smokers, thereby prolonging the harm caused by smoking. To investigate the molecular basis for this phenomenon, we conducted a genome-wide association study of DSM-IV nicotine withdrawal in a sample of African American (AA) and European American (EA) smokers. A combined AA and EA meta-analysis (n=8021) identified three highly correlated single nucleotide polymorphisms (SNPs) in the protocadherin (PCDH)-α, -ß and -γ gene cluster on chromosome 5 that were associated with nicotine withdrawal (P<5 × 10-8). We then studied one of the SNPs, rs31746, in an independent sample of smokers who participated in an intravenous nicotine infusion study that followed overnight smoking abstinence. After nicotine infusion, abstinent smokers with the withdrawal risk allele experienced greater alleviation of their urges to smoke, as assessed by the Brief Questionnaire on Smoking Urges (BQSU). Prior work has shown that the PCDH-α, -ß and -γ genes are expressed in neurons in a highly organized manner. We found that rs31746 mapped to a long-range neuron-specific enhancer element shown previously to regulate PCDH-α, -ß and -γ gene expression. Using Braincloud mRNA expression data, we identified a robust and specific association between rs31746 and PCDH-ß8 mRNA expression in frontal cortex tissue (P<1 × 10-5). We conclude that PCDH-α, -ß and -γ gene cluster regulatory variation influences the severity of nicotine withdrawal. Further studies on the PCDH-α, -ß and -γ genes and their role in nicotine withdrawal may inform the development of novel smoking cessation treatments and reduce the harm caused by tobacco smoking.
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Cadherinas/genética , Fumar/genética , Síndrome de Abstinencia a Sustancias/genética , Tabaquismo/genética , Adulto , Negro o Afroamericano/genética , Cadherinas/metabolismo , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Familia de Multigenes/genética , Nicotina/metabolismo , Polimorfismo de Nucleótido Simple/genética , Protocadherinas , Recurrencia , Cese del Hábito de Fumar , Población Blanca/genéticaRESUMEN
Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.
Asunto(s)
Abuso de Marihuana/genética , Fumar Marihuana/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígeno CD56/genética , Proteínas Portadoras/genética , Moléculas de Adhesión Celular/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Canales de Potasio/genética , Canales de potasio activados por Sodio , Adulto JovenRESUMEN
Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.
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Predisposición Genética a la Enfermedad , Trastornos Relacionados con Opioides/genética , Polimorfismo de Nucleótido Simple , Receptores AMPA/genética , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Animales , Femenino , Estudio de Asociación del Genoma Completo , Habituación Psicofisiológica/genética , Habituación Psicofisiológica/fisiología , Humanos , Masculino , Ratones Endogámicos , Trastornos Relacionados con Opioides/diagnóstico por imagen , Trastornos Relacionados con Opioides/fisiopatología , Receptores AMPA/metabolismo , Especificidad de la Especie , Adulto JovenRESUMEN
We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
Asunto(s)
Receptores Nicotínicos/genética , Tabaquismo/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Sitios de Empalme de ARN , Población Blanca/genéticaRESUMEN
Stress and hormones released in response to stress influence the effects of nicotine and the severity of nicotine withdrawal. Here, we systematically examine the contribution of a stress response gene, FKBP5, to the acute and chronic behavioral effects of nicotine in smokers. Subjects were European- and African-American (EA and AA) heavy smokers who participated in an intravenous (IV) nicotine administration study (total n=169). FKBP5 rs3800373 genotype was analyzed for association to several outcomes, including nicotine withdrawal and the acute subjective, heart rate (HR), blood pressure and plasma cortisol responses to IV nicotine. Nicotine withdrawal was also examined in relation to rs3800373 allele frequencies in an independent cohort of EA and AA current smokers (n=3821). For a subset of laboratory subjects FKBP5 mRNA (n=48) expression was explored for an association to the same outcomes. The rs3800373 minor allele was associated with less severe nicotine withdrawal in laboratory subjects and the independent cohort of smokers. The rs3800373 minor allele was also associated with lower subjective ratings of negative drug effects in response to IV nicotine. Low FKBP5 mRNA expression was associated lower cortisol levels, lower subjective ratings of negative drug effects and a blunted HR response to nicotine. Stress hormone regulation via FKBP5 warrants further investigation as a potential contributor to the effects of nicotine withdrawal, which occurs commonly, and has an important role in the maintenance of smoking behavior and relapse following a quit attempt.
Asunto(s)
Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fumar/genética , Proteínas de Unión a Tacrolimus/genética , Negro o Afroamericano , Alelos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Frecuencia de los Genes , Genotipo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/genética , Humanos , Hidrocortisona/sangre , Inyecciones Intravenosas , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , ARN/biosíntesis , ARN/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Síndrome de Abstinencia a Sustancias/fisiopatología , Población BlancaRESUMEN
We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.
Asunto(s)
Alcoholismo/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica/métodos , Adulto , Alcoholismo/epidemiología , Animales , Modelos Animales de Enfermedad , Femenino , Alemania/epidemiología , Humanos , Masculino , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple , Riesgo , Estados Unidos/epidemiologíaRESUMEN
Unbiased genome-wide approaches can provide novel insights into the biological pathways that are important for human behavior and psychiatric disorder risk. The association of α-endomannosidase gene (MANEA) variants and cocaine-induced paranoia (CIP) was initially described in a study that used a whole-genome approach. Behavioral effects have been reported for other mannosidase genes, but MANEA function in humans and the clinical potential of the previous findings remain unclear. We hypothesized that MANEA would be associated with psychiatric phenotypes unrelated to cocaine use. We used a multi-stage association study approach starting with four psychiatric disorders to show an association between a MANEA single-nucleotide polymorphism (SNP; rs1133503) and anxiety disorders. In the first study of 2073 European American (EA) and 2459 African American subjects mostly with comorbid drug or alcohol dependence, we observed an association in EAs of rs1133503 with panic disorder (PD) (191 PD cases, odds ratio (OR)=1.7 (95% confidence interval (CI): 1.22-2.41), P=0.002). We replicated this finding in an independent sample of 142 PD cases (OR =1.53 (95% CI: 1.00-2.31), P=0.043) and extended it in an independent sample of 131 generalized social anxiety disorder cases (OR=2.15 (95% CI: 1.27-3.64), P=0.004). MANEA alleles and genotypes were also associated with gene expression differences in whole blood cells. Using publically available data, we observed a consistent effect on expression in brain tissue. We conclude that pathways involving α-endomannosidase warrant further investigation in relation to anxiety disorders.
Asunto(s)
Negro o Afroamericano/genética , Estudio de Asociación del Genoma Completo , Manosidasas/genética , Proteínas de la Membrana/genética , Trastorno de Pánico/genética , Trastornos Fóbicos/genética , Población Blanca/genética , Adulto , Negro o Afroamericano/estadística & datos numéricos , Células Sanguíneas/metabolismo , Encéfalo/metabolismo , Comorbilidad , Femenino , Expresión Génica/genética , Humanos , Masculino , Manosidasas/metabolismo , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Trastorno de Pánico/epidemiología , Trastornos Fóbicos/epidemiología , Polimorfismo de Nucleótido Simple/genética , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/genética , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10(-31); AAs: Arg369Cys, P=6.33 × 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 × 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10(-11)), PDLIM5 in EAs (P=2.01 × 10(-8)), and METAP in AAs (P=3.35 × 10(-8)). We also identified a novel GWS association (1.17 × 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.
Asunto(s)
Alcoholismo/epidemiología , Alcoholismo/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Proteínas de Microfilamentos/genética , Proteínas de Transporte Vesicular/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Negro o Afroamericano/genética , Alcohol Deshidrogenasa/genética , Aminopeptidasas/genética , Mapeo Cromosómico , Estudios de Cohortes , Factores Eucarióticos de Iniciación/genética , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Proteínas con Dominio LIM/genética , Masculino , Proteínas Mitocondriales/genética , Polimorfismo de Nucleótido Simple/genética , Escalas de Valoración Psiquiátrica , Estados Unidos/epidemiología , Población Blanca/genéticaRESUMEN
We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8 90 000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B ('family with sequence similarity 53, member B') locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 × 10(-8). The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 × 10(-9) in the EA discovery sample. SNP rs2456778, which maps to CDK1 ('cyclin-dependent kinase 1'), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 × 10(-8)). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies.
Asunto(s)
Negro o Afroamericano/genética , Trastornos Relacionados con Cocaína/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto , Proteína Quinasa CDC2 , Cocaína/efectos adversos , Quinasas Ciclina-Dependientes/genética , Inhibidores de Captación de Dopamina/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Masculino , Co-Represor 2 de Receptor Nuclear/genética , Trastornos Paranoides/inducido químicamente , Trastornos Paranoides/genética , Estados UnidosRESUMEN
In prior work, congenic strains carrying the DBA/2Igb (D2) region of chromosome 2 (Chr2) for alcohol preference were bred onto a C57BL/6Ibg (B6) background and as predicted were found to reduce voluntary consumption. Subsequently, interval-specific congenic recombinant strains (ISCRS) were generated and also tested. These ISCRS strains reduced the quantitative trait loci (QTL) interval to a comparatively small 3.4 Mb region. Here, we have exploited an integrative approach using both murine and human populations to critically evaluate candidate genes within this region. First, we used bioinformatics tools to search for genes relevant to alcohol preference within the QTL region. Second, we searched for single nucleotide polymorphisms (SNPs) within exons of every gene in this region. Third, we conducted follow-up microarray analyses to identify differentially expressed genes between the B6 and ISCRS strains in mice from each group. Fourth, we analyzed correlations between the expression level of candidate genes and phenotypes of alcohol preference in a large family of BXD recombinant inbred strains derived from B6 and D2. Finally, we evaluated SNP segregation in both BXD mouse strains and in humans who were heavy alcohol drinkers or non-drinkers. Among several potential candidate genes in this region, we identified activating transcription factor 2 (Atf2) as the most plausible gene that would influence alcohol preference. However, the candidacy of Atf2 was only weakly supported when we used a genetic network approach and by focused reanalysis of genome-wide association study data from European-American and African-American populations. Thus, we cannot conclude that Atf2 plays a role in the regulation of the QTL of mouse Chr2.
Asunto(s)
Factor de Transcripción Activador 2/genética , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Factor de Transcripción Activador 2/metabolismo , Animales , Secuencia de Bases , Cromosomas Humanos Par 2 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ADN , TranscriptomaAsunto(s)
Polimorfismo de Nucleótido Simple , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/fisiología , Trastornos por Estrés Postraumático/genética , Adulto , Factores de Edad , Anciano , Población Negra/genética , Estudios de Cohortes , Femenino , Genotipo , Humanos , Modelos Logísticos , Masculino , Menopausia , Persona de Mediana Edad , Estudios Prospectivos , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Riesgo , Tamaño de la Muestra , Sesgo de Selección , Factores Socioeconómicos , Trastornos por Estrés Postraumático/etnología , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/genética , Estados Unidos/epidemiología , Población Blanca/genéticaRESUMEN
SIGNIFICANCE: Given the substantial health risks of smoking during pregnancy, and the potential of pharmacotherapy to enhance quit rates, a need exists to examine the utility of pharmacotherapy for smoking cessation during pregnancy. LITERATURE REVIEW: We briefly review the first-line medications that are recommended for smoking cessation in nonpregnant adults. Additionally, we review the toxicity of tobacco smoke and the potential risks of pharmacotherapy as evidenced by animal studies. We review in more detail studies conducted in pregnant women, including (a) observational studies, (b) short-term safety and longer term uncontrolled studies, and (c) randomized controlled clinical trials (both effectiveness and efficacy studies). DISCUSSION: Because the safety and efficacy of pharmacotherapy for smoking cessation during pregnancy have not been established, no definitive recommendations can be made on the topic. Effectiveness trials have shown that nicotine replacement therapy (NRT) enhances smoking cessation during pregnancy, but efficacy trials have not shown an advantage for NRT compared with placebo treatment. Small sample size or poor medication compliance (with either the dose or the duration of treatment) may contribute to lack of efficacy in placebo-controlled NRT trials. However, these trials showed that NRT did not adversely affect birth outcomes and increased birth weight. Based on these findings and the fact that all medications have some risk, psychosocial interventions should be the first treatment option for pregnant smokers. Additional research is needed to determine fully the risks and benefits of the various pharmacotherapies for smoking cessation during pregnancy.
Asunto(s)
Quimioterapia/métodos , Cese del Hábito de Fumar/métodos , Fumar/efectos adversos , Fumar/tratamiento farmacológico , Animales , Benzazepinas/uso terapéutico , Bupropión/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Nicotina/uso terapéutico , Embarazo , Quinoxalinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , VareniclinaRESUMEN
Non-coding regulatory elements can transduce the human genome's response to environmental stimuli. Thus, there is a possibility that variation in non-coding regulatory elements may underlie some of the diversity in human behavior. However, this idea has remained largely untested due to the difficulty in accurately identifying regulatory elements in the 98% of the human genome that does not encode protein. The recent recognition that small trans-acting RNAs anneal to mRNA and regulate gene expression provides a means to identify and test such variants. Here, we show that microRNA-directed silencing of mRNA can be attenuated by a common human polymorphism. We have identified an element (A-element) within serotonin receptor 1B (HTR1B) mRNA that confers repression by miR-96. The repressive activity of this element is attenuated by a common human variant (G-element) that disrupts a nucleotide critical for its interaction with miR-96. Because deletion of the HTR1B gene leads to an aggressive phenotype in mice, we hypothesized an association between the A/G polymorphism and aggressive phenotypes in a sample of 359 college students. As predicted, individuals homozygous for the ancestral A-element reported more conduct-disorder behaviors than individuals with the G-element. Our studies suggest that such functional variants may be common and may help to refine the search for genes involved in complex behavioral disorders.
Asunto(s)
Agresión/fisiología , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , MicroARNs/fisiología , Polimorfismo Genético/genética , ARN Mensajero/genética , Receptor de Serotonina 5-HT1B/genética , Etnicidad/genética , Femenino , Genotipo , Células HeLa , Humanos , Luciferasas/genética , Masculino , Datos de Secuencia Molecular , Análisis de Secuencia de ARN , Factores Sexuales , Transfección/métodosRESUMEN
Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P<0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (chi(2)=14.82, degrees of freedom (d.f.)=1, P<0.001), CD (chi(2)=9.19, d.f.=1, P=0.002) and OD (chi(2)=20.68, d.f.=1, P<0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P=0.03, beta=1.86, odds ratio (OR)=6.43) and especially on OD (P<0.001, beta=3.92, OR=50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (chi(2)=8.12, d.f.=1, P=0.004). Logistic regression analyses also revealed its risk effect on AD (P=0.009, beta=1.06, OR=2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.