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1.
Transl Psychiatry ; 8(1): 190, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217971

RESUMO

Family and twin studies have shown a genetic component to seasonal affective disorder (SAD). A number of candidate gene studies have examined the role of variations within biologically relevant genes in SAD susceptibility, but few genome-wide association studies (GWAS) have been performed to date. The authors aimed to identify genetic risk variants for SAD through GWAS. The authors performed a GWAS for SAD in 1380 cases and 2937 controls of European-American (EA) origin, selected from samples for GWAS of major depressive disorder and of bipolar disorder. Further bioinformatic analyses were conducted to examine additional genomic and biological evidence associated with the top GWAS signals. No susceptibility loci for SAD were identified at a genome-wide significant level. The strongest association was at an intronic variant (rs139459337) within ZBTB20 (odds ratio (OR) = 1.63, p = 8.4 × 10-7), which encodes a transcriptional repressor that has roles in neurogenesis and in adult brain. Expression quantitative trait loci (eQTL) analysis showed that the risk allele "T" of rs139459337 is associated with reduced mRNA expression of ZBTB20 in human temporal cortex (p = 0.028). Zbtb20 is required for normal murine circadian rhythm and for entrainment to a shortened day. Of the 330 human orthologs of murine genes directly repressed by Zbtb20, there were 32 associated with SAD in our sample (at p < 0.05), representing a significant enrichment of ZBTB20 targets among our SAD genetic association signals (fold = 1.93, p = 0.001). ZBTB20 is a candidate susceptibility gene for SAD, based on a convergence of genetic, genomic, and biological evidence. Further studies are necessary to confirm its role in SAD.


Assuntos
Estudo de Associação Genômica Ampla , Proteínas do Tecido Nervoso/genética , Transtorno Afetivo Sazonal/genética , Fatores de Transcrição/genética , População Branca/genética , Alelos , Transtorno Bipolar/genética , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos
2.
Mol Neuropsychiatry ; 3(1): 1-11, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28879196

RESUMO

Suicidal behavior is a complex and devastating phenotype with a heritable component that has not been fully explained by existing common genetic variant analyses. This study represents the first large-scale DNA sequencing project designed to assess the role of rare functional genetic variation in suicidal behavior risk. To accomplish this, whole-exome sequencing data for ∼19,000 genes were generated for 387 bipolar disorder subjects with a history of suicide attempt and 631 bipolar disorder subjects with no prior suicide attempts. Rare functional variants were assessed in all exome genes as well as pathways hypothesized to contribute to suicidal behavior risk. No result survived conservative Bonferroni correction, though many suggestive findings have arisen that merit additional attention. In addition, nominal support for past associations in genes, such as BDNF, and pathways, such as the hypothalamic-pituitary-adrenal axis, was also observed. Finally, a novel pathway was identified that is driven by aldehyde dehydrogenase genes. Ultimately, this investigation explores variation left largely untouched by existing efforts in suicidal behavior, providing a wealth of novel information to add to future investigations, such as meta-analyses.

3.
Epigenetics ; 10(7): 581-96, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25985232

RESUMO

Methyl-Seq was recently developed as a targeted approach to assess DNA methylation (DNAm) at a genome-wide level in human. We adapted it for mouse and sought to examine DNAm differences across liver and 2 brain regions: cortex and hippocampus. A custom hybridization array was designed to isolate 99 Mb of CpG islands, shores, shelves, and regulatory elements in the mouse genome. This was followed by bisulfite conversion and sequencing on the Illumina HiSeq2000. The majority of differentially methylated cytosines (DMCs) were present at greater than expected frequency in introns, intergenic regions, near CpG islands, and transcriptional enhancers. Liver-specific enhancers were observed to be methylated in cortex, while cortex specific enhancers were methylated in the liver. Interestingly, commonly shared enhancers were differentially methylated between the liver and cortex. Gene ontology and pathway analysis showed that genes that were hypomethylated in the cortex and hippocampus were enriched for neuronal components and neuronal function. In contrast, genes that were hypomethylated in the liver were enriched for cellular components important for liver function. Bisulfite-pyrosequencing validation of 75 DMCs from 19 different loci showed a correlation of r = 0.87 with Methyl-Seq data. We also identified genes involved in neurodevelopment that were not previously reported to be differentially methylated across brain regions. This platform constitutes a valuable tool for future genome-wide studies involving mouse models of disease.


Assuntos
Encéfalo/crescimento & desenvolvimento , Metilação de DNA , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Animais , Encéfalo/metabolismo , Ilhas de CpG , Citidina/análogos & derivados , Citidina/química , Elementos Facilitadores Genéticos , Córtex Entorrinal/química , Córtex Entorrinal/metabolismo , Hipocampo/química , Hipocampo/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Sulfitos/química
4.
Psychosomatics ; 55(5): 485-90, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24746452

RESUMO

BACKGROUND: In prior work, we identified a relationship between symptom burden and vascular outcomes in bipolar disorder. OBJECTIVE: We sought to replicate these findings using a readily accessible measure of mood disorder chronicity and vascular mortality. METHODS: We conducted a mortality assessment using the National Death Index for 1716 participants with bipolar I disorder from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium. We assessed the relationship between the duration of the most severe depressive and manic episodes and time to vascular mortality (cardiovascular or cerebrovascular) using Cox proportional hazards models, adjusting for potentially confounding variables. RESULTS: Mortality was assessed a mean for 7 years following study intake, at which time 58 participants died, 18 of vascular causes. These participants had depression for much longer than their counterparts did (Wilcoxon rank sum Z = 2.30, p = 0.02) and the duration of the longest depressive episode in years was significantly associated with time to vascular mortality in models (hazard ratio = 1.16, 95% confidence interval: 1.02-1.33, p = 0.02), which controlled for age, gender, vascular disease equivalents, and vascular disease risk factors. The duration of longest mania was not related to vascular mortality. CONCLUSION: The duration of the most severe depression is independently predictive of vascular mortality, lending further support to the idea that mood disorders hasten vascular mortality in a dose-dependent fashion. Further study of the relevant mechanisms by which mood disorders may hasten vascular disease and of integrated treatments for mood and cardiovascular risk factors is warranted.


Assuntos
Transtorno Bipolar/complicações , Doenças Vasculares/mortalidade , Adulto , Transtorno Bipolar/genética , Causas de Morte , Feminino , Genômica , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Fatores de Risco
5.
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.

6.
Psychiatry Res ; 200(2-3): 1044-6, 2012 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-22766010

RESUMO

We report the results of a high-density attempted suicide association study of the X chromosome, which genotyped 23,141 SNPs on 983 attempters and 1143 non-attempters and generated modest evidence for association for SH3KBP1 (P=1.07×10(-4)) and GRIA3 (P=4.01×10(-4)). These findings highlight the need for larger sample sets and meta-analytic approaches.


Assuntos
Cromossomos Humanos X/genética , Polimorfismo de Nucleotídeo Único , Tentativa de Suicídio , Adulto , Transtorno Bipolar/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Transtornos Psicóticos/genética , Fatores de Risco
7.
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
8.
Am J Med Genet B Neuropsychiatr Genet ; 159B(1): 112-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22170779

RESUMO

Epidemiological studies, such as family, twin, and adoption studies, demonstrate the presence of a heritable component to both attempted and completed suicide. Some of this heritability is accounted for by the presence of comorbid psychiatric disorders, but the evidence also indicates that a portion of this heritability is specific to suicidality. The serotonergic system has been studied extensively in this phenotype, but findings have been inconsistent, possibly due to the presence of multiple susceptibility variants and/or gene-gene interactions. In this study, we genotyped 174 tag and coding single nucleotide polymorphisms (SNPs) from 17 genes within the serotonin pathway on 516 subjects with a major mood disorder and a history of a suicide attempt (cases) and 515 healthy controls, with the goal of capturing the common genetic variation across each of these candidate genes. We tested the 174 markers in single-SNP, haplotype, gene-based, and epistasis analyses. While these association analyses identified multiple marginally significant SNPs, haplotypes, genes, and interactions, none of them survived correction for multiple testing. Additional studies, including assessment in larger sample sets and deep resequencing to identify rare causal variants, may be required to fully understand the role that the serotonin pathway plays in suicidal behavior.


Assuntos
Estudos de Associação Genética , Serotonina/genética , Transdução de Sinais/genética , Tentativa de Suicídio , Humanos , Polimorfismo de Nucleotídeo Único/genética , Tentativa de Suicídio/psicologia , Transmissão Sináptica/genética
9.
Am J Med Genet B Neuropsychiatr Genet ; 153B(5): 1016-23, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20468057

RESUMO

Family, twin, and adoption studies provide convincing evidence for a genetic contribution to suicidal behavior. The heritability for suicidal behavior depends in part on the transmission of psychiatric disorders, such as mood disorders and substance use disorders, but is also partly independent of them. Three linkage studies using the attempted suicide phenotype in pedigrees with bipolar disorder, major depression, or alcoholism have provided consistent evidence that 2p11-12 harbors a susceptibility gene for attempted suicide. A microarray expression study using postmortem brain samples has implicated a gene from the 2p11-12 candidate region, the trans-Golgi network protein 2 (TGOLN2) gene, as being consistently up-regulated in suicide cases as compared to controls. Here, we present a TGOLN2 case-control association study using nine single nucleotide polymorphisms (SNPs). These nine SNPs, which include seven tag SNPs and two coding SNPs, have been genotyped in 517 mood disorder subjects with a history of attempted suicide and 515 normal controls. Allelic and genotypic analyses of the case-control sample did not provide evidence for association with the attempted suicide phenotype. Eight of the nine SNPs provided supportive evidence for association (P-values ranging from 0.008 to 0.03) when we compared the attempted suicide cases with a history of alcoholism to the attempted suicide cases without a history of alcoholism. However, this association finding was not replicated in an independent sample. Taken together, these analyses do not provide support for the hypothesis that common genetic variation in TGOLN2 contributes significantly to the risk for attempted suicide in subjects with major mood disorders.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Glicoproteínas de Membrana/genética , Tentativa de Suicídio , Adulto , Alcoolismo/complicações , Alcoolismo/genética , Alelos , Estudos de Casos e Controles , Feminino , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
10.
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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