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1.
Mol Psychiatry ; 23(5): 1293-1302, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29112194

RESUMO

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.

2.
Psychol Med ; 46(11): 2385-96, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27291060

RESUMO

BACKGROUND: White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. METHOD: WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. RESULTS: This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. CONCLUSIONS: Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD - a group at particular risk of future hypo/manic episodes - suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.


Assuntos
Transtorno Bipolar/patologia , Corpo Caloso/patologia , Transtorno Depressivo Maior/patologia , Imagem de Tensor de Difusão/métodos , Substância Branca/patologia , Adolescente , Adulto , Transtorno Bipolar/diagnóstico por imagem , Criança , Corpo Caloso/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Masculino , Recidiva , Substância Branca/diagnóstico por imagem , Adulto Jovem
3.
Psychol Med ; 45(10): 2181-96, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25823794

RESUMO

BACKGROUND: The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD: A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS: The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS: The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.


Assuntos
Transtorno Bipolar/psicologia , Família/psicologia , Predisposição Genética para Doença , Controle Interno-Externo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , National Institute of Mental Health (U.S.) , Estados Unidos , Adulto Jovem
4.
Transl Psychiatry ; 5: e558, 2015 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-25918995

RESUMO

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.


Assuntos
Transtorno da Personalidade Antissocial/genética , Encéfalo/metabolismo , Interferon Tipo I/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Alcoolismo/genética , Estudos de Casos e Controles , Transtornos Relacionados ao Uso de Cocaína/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
5.
N Engl J Med ; 368(23): 2169-81, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23738544

RESUMO

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/antagonistas & inibidores , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Microangiopatias Trombóticas/prevenção & controle , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Terapia Combinada , Feminino , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/terapia , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Troca Plasmática , Contagem de Plaquetas , Qualidade de Vida , Adulto Jovem
6.
Genes Brain Behav ; 12(5): 532-42, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23607416

RESUMO

Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10(-3) and 2.08 × 10(-4) for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF < 0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.


Assuntos
Afro-Americanos/genética , Alcoolismo/genética , Grupo com Ancestrais do Continente Europeu/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Adulto , Alcoolismo/etnologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo Genético , Estados Unidos
7.
Mol Psychiatry ; 18(11): 1218-24, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23089632

RESUMO

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.


Assuntos
Alcoolismo/genética , Cromossomos Humanos Par 15/genética , Estudo de Associação Genômica Ampla , Fases de Leitura Aberta/genética , Avaliação de Sintomas , Alcoolismo/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Endofenótipos , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único
8.
Mol Psychiatry ; 18(3): 340-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22212596

RESUMO

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Cerebelo/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genética
9.
Herz ; 37(7): 735-41, 2012 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-23052901

RESUMO

Hypertension is one of the most frequent cardiovascular diseases in industrial countries. Traditionally blood pressure measurements are obtained using pressure cuffs from the upper limbs. There is increasing evidence supporting the clinical value of the central blood pressure. In comparison to peripheral blood pressure, central blood pressure more strongly predicts future cardiovascular events. In addition, antihypertensive treatment lowers peripheral and central blood pressure differently. This effect may contribute to the distinct effects on cardiovascular mortality observed between different antihypertensive drugs. Increasingly, commercially available devices are in use for non-invasive measurement of central hemodynamic parameters. In the present overview the physiological and pathophysiological role of central blood pressure in hypertension is summarized. Non-invasive techniques are illustrated and the predictive value of central blood pressure in hypertension is discussed.


Assuntos
Determinação da Pressão Arterial/métodos , Pressão Sanguínea , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Humanos
10.
Transl Psychiatry ; 2: e156, 2012 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-22948381

RESUMO

A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Proteínas de Membrana/genética , Transtorno de Pânico/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino
11.
Mol Psychiatry ; 17(9): 887-905, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22584867

RESUMO

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.


Assuntos
Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/genética , Genômica/estatística & dados numéricos , Esquizofrenia/genética , Animais , Estudos de Casos e Controles , Bases de Dados Genéticas/estatística & dados numéricos , Modelos Animais de Doenças , Genômica/métodos , Humanos , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/diagnóstico
12.
Genes Brain Behav ; 11(6): 712-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22554406

RESUMO

Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634 583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10(-10)). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon four, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.


Assuntos
Lobo Frontal/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Estudo de Associação Genômica Ampla/métodos , Ritmo Teta/genética , Adolescente , Adulto , Idoso , Alcoolismo/genética , Criança , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Ritmo Teta/fisiologia , Adulto Jovem
13.
Mol Psychiatry ; 17(8): 818-26, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21769101

RESUMO

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.


Assuntos
Transtorno Bipolar/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Transtornos Psicóticos/genética , Transtorno Bipolar/complicações , Transtorno Depressivo Maior/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/complicações
14.
Mol Psychiatry ; 17(4): 445-50, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21968928

RESUMO

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
15.
Am J Med Genet B Neuropsychiatr Genet ; 156B(5): 569-80, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21595007

RESUMO

To examine if ethnic differences in concerns about unfavorable consequences from psychiatric genetic studies, existing between non-Hispanic Black and White populations, persist among participants in an actual genetic study of bipolar disorder. Historically, minority subjects have been less willing to participate in such studies. Participants in the US Bipolar Genome Study (BIGS) were assessed on six items of concerns in the Questionnaire on Genetic Risk (QGR). Each item had five response categories, ranging from "not at all" concerned to "very concerned." Responses from Black (N = 188) and White participants (N = 1,065) formed the base for this analysis. Concerns about unfavorable consequences of conducting psychiatric genetic studies were prevalent in the whole sample. Concern for medical insurance was most prevalent (63.4%), followed by job concern (58.8%) and stigma (57.4%). Racial discrimination was less prevalent (28.1%). Blacks endorsed significantly stronger concerns for all consequences except the medical insurance item (P < 0.008). The most significant ethnic disparity in concerns was for racial discrimination (P < 0.0001). Associations between levels of concern and ethnicity remained significant after adjustments for other factors in multivariate models. Ethnic differences (Blacks vs. Whites) in perceived concerns about unfavorable consequences from participation persist among participants in an actual psychiatric genetic study. This suggests that other factors may play a more critical role in the decision not to participate. Future studies should investigate more comprehensive sources of barriers to consenting for ongoing psychiatric genetic studies in representative samples, incorporating assessments from non-participants as well as participants.


Assuntos
Transtorno Bipolar/genética , Adulto , Afro-Americanos/etnologia , Atitude/etnologia , Transtorno Bipolar/etnologia , Emprego , Grupo com Ancestrais do Continente Europeu , Feminino , Acesso aos Serviços de Saúde/estatística & dados numéricos , Humanos , Seguro Saúde , Masculino , Pessoa de Meia-Idade , Percepção/ética , Preconceito , Privacidade , Opinião Pública , Risco , Inquéritos e Questionários
16.
Mol Psychiatry ; 16(1): 37-58, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19935739

RESUMO

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.


Assuntos
Biomarcadores/sangue , Delusões/genética , Genômica/métodos , Alucinações/genética , Transtornos Psicóticos/genética , Adulto , Estudos de Casos e Controles , Delusões/sangue , Delusões/complicações , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Alucinações/sangue , Alucinações/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/sangue , Transtornos Psicóticos/complicações , Esquizofrenia/sangue , Esquizofrenia/complicações , Esquizofrenia/genética
17.
Mol Psychiatry ; 16(8): 800-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20585324

RESUMO

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N = 872 with CD and N = 3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10(-8)) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.


Assuntos
Alcoolismo/genética , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idoso , Alcoolismo/complicações , Estudos de Casos e Controles , Transtorno da Conduta/complicações , Diagnóstico Duplo (Psiquiatria)/métodos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos
18.
Am J Med Genet B Neuropsychiatr Genet ; 153B(4): 850-77, 2010 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-20468069

RESUMO

We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.


Assuntos
Transtorno Bipolar/genética , Genômica/métodos , Expressão Gênica , Genes , Humanos , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Fatores de Risco , Transdução de Sinais/genética
19.
Dtsch Med Wochenschr ; 135 Suppl 1: S4-14, 2010 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-20180172
20.
Psychol Med ; 40(9): 1549-58, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19951450

RESUMO

BACKGROUND: There is considerable debate surrounding the effective measurement of DSM-IV symptoms used to assess manic disorders in epidemiological samples. METHOD: Using two nationally representative datasets, the National Epidemiological Survey of Alcohol and Related Conditions (NESARC, n=43,093 at wave 1, n=34,653 at 3-year follow-up) and the National Comorbidity Survey - Replication (NCS-R, n=9282), we examined the psychometric properties of symptoms used to assess DSM-IV mania. The predictive utility of the mania factor score was tested using the 3-year follow-up data in NESARC. RESULTS: Criterion B symptoms were unidimensional (single factor) in both samples. The symptoms assessing flight of ideas, distractibility and increased goal-directed activities had high factor loadings (0.70-0.93) with moderate rates of endorsement, thus providing good discrimination between individuals with and without mania. The symptom assessing grandiosity performed less well in both samples. The quantitative mania factor score was a good predictor of more severe disorders at the 3-year follow-up in the NESARC sample, even after controlling for a past history of DSM-IV diagnosis of manic disorder. CONCLUSIONS: These analyses suggest that questions based on some DSM symptoms effectively discriminate between individuals at high and low liability to mania, but others do not. A quantitative mania factor score may aid in predicting recurrence for patients with a history of mania. Methods for assessing mania using structured interviews in the absence of clinical assessment require further refinement.


Assuntos
Transtorno Bipolar/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/psicologia , Análise Fatorial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Estados Unidos/epidemiologia
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