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1.
Front Genet ; 4: 87, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23730306

RESUMO

Genome-wide association studies (GWAS) have implicated ANK3 as a susceptibility gene for bipolar disorder (BP). We examined whether epistasis with ANK3 may contribute to the "missing heritability" in BP. We first identified via the STRING database 14 genes encoding proteins with prior biological evidence that they interact molecularly with ANK3. We then tested for statistical evidence of interactions between SNPs in these genes in association with BP in a discovery GWAS dataset and two replication GWAS datasets. The most significant interaction in the discovery GWAS was between SNPs in ANK3 and KCNQ2 (p = 3.18 × 10(-8)). A total of 31 pair-wise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pair-wise interactions were significant in the first replication GWAS. None were significant in the second replication GWAS, but the two SNPs from KCNQ2 were found to significantly interact with five other SNPs in ANK3, suggesting possible allelic heterogeneity. KCNQ2 forms homo- and hetero-meric complexes with KCNQ3 that constitute voltage-gated potassium channels in neurons. ANK3 is an adaptor protein that, through its interaction with KCNQ2 and KCNQ3, directs the localization of this channel in the axon initial segment (AIS). At the AIS, the KCNQ2/3 complex gives rise to the M-current, which stabilizes the neuronal resting potential and inhibits repetitive firing of action potentials. Thus, these channels act as "dampening" components and prevent neuronal hyperactivity. The interactions between ANK3 and KCNQ2 merit further investigation, and if confirmed, may motivate a new line of research into a novel therapeutic target for BP.

2.
Psychopharmacology (Berl) ; 227(2): 231-41, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23274505

RESUMO

RATIONALE: Chronic dysregulation of hypothalamus-pituitary-adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins, FKBP5 and CRHR1, have been associated with several neuropsychiatric disorders. OBJECTIVES: We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined. METHODS: A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in FKBP5 and four in CRHR1 were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables. RESULTS: The strongest association was for rs4713902 in FKBP5 with baseline cortisol (p dom = 0.0004). We also identified a male-specific effect of FKBP5 polymorphisms on peak response and response area under the curve (p = 0.0028 for rs3800374). In CRHR1, rs7209436, rs110402, and rs242924 were nominally associated with peak response (p rec = 0.0029-0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in CRHR1 in association with baseline cortisol (p LRT = 0.0272 and p LRT = 0.0483, respectively). CONCLUSIONS: We show association of variants in FKBP5 and CRHR1 with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders.


Assuntos
Hidrocortisona/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Estresse Psicológico/fisiopatologia , Proteínas de Ligação a Tacrolimo/genética , Adolescente , Adulto , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo de Nucleotídeo Único , Testes Psicológicos , Saliva/metabolismo , Fatores Sexuais , Estresse Psicológico/genética , Fatores de Tempo , Adulto Jovem
3.
Am J Med Genet B Neuropsychiatr Genet ; 159B(5): 508-18, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22573399

RESUMO

Numerous candidate gene association studies of bipolar disorder (BP) have been carried out, but the results have been inconsistent. Individual studies are typically underpowered to detect associations with genes of small effect sizes. We conducted a meta-analysis of published candidate gene studies to evaluate the cumulative evidence. We systematically searched for all published candidate gene association studies of BP. We then carried out a random-effects meta-analysis on all polymorphisms that were reported on by three or more case-control studies. The results from meta-analyses of these genes were compared with the findings from a recent mega-analysis of eleven genome-wide association studies (GWAS) in BP performed by the Psychiatric GWAS Consortium (PGC). A total of 487 articles were included in our review. Among these, 33 polymorphisms in 18 genes were reported on by three or more case-control studies and included in the random-effects meta-analysis. Polymorphisms in BDNF, DRD4, DAOA, and TPH1, were found to be nominally significant with a P-value < 0.05. However, none of the findings were significant after correction for multiple testing. Moreover, none of these polymorphisms were nominally significant in the PGC-BP GWAS. A number of plausible candidate genes have been previously associated with BP. However, the lack of robust findings in our review of these candidate genes highlights the need for more atheoretical approaches to study the genetics of BP afforded by GWAS. The results of this meta-analysis and from other on-going genomic experiments in BP are available online at Metamoodics (http://metamoodics.igm.jhmi.edu).


Assuntos
Transtorno Bipolar/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo Genético
4.
Schizophr Res ; 138(2-3): 188-91, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22559949

RESUMO

Meta-analyses report larger amygdala in subjects with bipolar disorder compared to schizophrenia. However, few studies have compared the size of amygdala in psychotic bipolar disorder with schizophrenia. Here we examine size of amygdala in a sample of 36 patients with psychotic bipolar disorder, 31 patients with schizophrenia and 27 healthy comparison subjects. Patients with schizophrenia had smaller amygdala compared with patients with psychotic bipolar disorder (p=0.014). These results suggest that change in volume of amygdala may represent a morphologic feature distinguishing psychotic bipolar disorder from schizophrenia.


Assuntos
Tonsila do Cerebelo/patologia , Transtorno Bipolar/patologia , Esquizofrenia/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão
5.
Biol Psychiatry ; 68(9): 801-10, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20723887

RESUMO

BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis. METHODS: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). RESULTS: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10⁻4, 2.1 × 10⁻4; p(corrected) = .03, .04) and were consistent across two large datasets. CONCLUSIONS: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.


Assuntos
Canais de Cálcio Tipo L/genética , Predisposição Genética para Doença/genética , Transtornos do Humor/diagnóstico , Transtornos do Humor/genética , Animais , Comportamento Animal/efeitos dos fármacos , Dextroanfetamina/farmacologia , Modelos Animais de Doenças , Feminino , Haploinsuficiência , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais
6.
Am J Psychiatry ; 166(11): 1229-37, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19755578

RESUMO

OBJECTIVE: Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD: Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS: The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z(LR)) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z(LR) of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z(LR)=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS: This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.


Assuntos
Transtorno Bipolar/genética , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/genética , Transtorno Depressivo Maior/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Adulto , Transtorno Bipolar/diagnóstico , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Transtorno Depressivo Maior/diagnóstico , Feminino , Seguimentos , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Repetições de Microssatélites , Pessoa de Meia-Idade , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
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