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1.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

2.
Nat Genet ; 52(4): 437-447, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231276

RESUMO

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Transtorno Bipolar/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e Especificidade
3.
Biol Psychiatry ; 87(5): 419-430, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570195

RESUMO

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

4.
Front Genet ; 10: 870, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31620172

RESUMO

Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/ß-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD.

5.
Biol Psychiatry ; 82(5): 322-329, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28049566

RESUMO

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.


Assuntos
Depressão/genética , Transtorno Depressivo/genética , Loci Gênicos , Predisposição Genética para Doença , Hidrolases Anidrido Ácido/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Neoplasias/genética , Fenótipo
6.
Biol Psychiatry ; 81(4): 325-335, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27519822

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Idade de Início , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto Jovem
7.
Biol Psychiatry ; 77(1): 29-35, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25483343

RESUMO

Clinicians already face "personalized" medicine every day while experiencing the great variation in toxicities and drug efficacy among individual patients. Pharmacogenetics studies are the platform for discovering the DNA determinants of variability in drug response and tolerability. Research now focuses on the genome after its beginning with analyses of single genes. Therapeutic outcomes from several psychotropic drugs have been weakly linked to specific genetic variants without independent replication. Drug side effects show stronger associations to genetic variants, including human leukocyte antigen loci with carbamazepine-induced dermatologic outcome and MC4R with atypical antipsychotic weight gain. Clinical implementation has proven challenging, with barriers including a lack of replicable prospective evidence for clinical utility required for altering medical care. More recent studies show promising approaches for reducing these barriers to routine incorporation of pharmacogenetics data into clinical care.


Assuntos
Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Farmacogenética/tendências , Psicotrópicos/uso terapêutico , Variação Genética , História do Século XX , História do Século XXI , Humanos , Farmacogenética/história , Medicina de Precisão , Psicotrópicos/efeitos adversos , Resultado do Tratamento
8.
Neuron ; 84(5): 940-53, 2014 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-25467980

RESUMO

Little is known about genetic mechanisms that regulate the ratio of cortical excitatory and inhibitory neurons. We show that NPAS1 and NPAS3 transcription factors (TFs) are expressed in progenitor domains of the mouse basal ganglia (subpallium, MGE, and CGE). NPAS1(-/-) mutants had increased proliferation, ERK signaling, and expression of Arx in the MGE and CGE. NPAS1(-/-) mutants also had increased neocortical inhibition (sIPSC and mIPSC) and generated an excess of somatostatin(+) (SST) (MGE-derived) and vasoactive intestinal polypeptide(+) (VIP) (CGE-derived) neocortical interneurons, but had a normal density of parvalbumin(+) (PV) (MGE-derived) interneurons. In contrast, NPAS3(-/-) mutants showed decreased proliferation and ERK signaling in progenitors of the ganglionic eminences and had fewer SST(+) and VIP(+) interneurons. NPAS1 repressed activity of an Arx enhancer, and Arx overexpression resulted in increased proliferation of CGE progenitors. These results provide insights into genetic regulation of cortical interneuron numbers and cortical inhibitory tone.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Interneurônios/classificação , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Transtorno Autístico/genética , Transtorno Autístico/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células/genética , Células Cultivadas , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Neuropsychopharmacology ; 39(10): 2423-31, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24755890

RESUMO

Panic disorder (PD) is a debilitating anxiety disorder characterized by episodes of intense fear with autonomic and psychological symptoms that lead to behavioral impairment. A convergence of genetic and biological evidence implicates gamma-aminobutyric acid type A receptor subunits on chromosome 15q12 as candidate genes for PD. This study investigated 120 Caucasian, multiplex PD pedigrees using regional microsatellites (chr15q11-13) and found support for linkage (logarithm of odds (LOD) ⩾2), with a prominent parent-of-origin effect. Genotyping with 10 single-nucleotide polymorphisms (SNPs) showed linkage to GABRB3 (rs11631421, LOD=4.6) and GABRA5 (rs2075716, LOD=2.2), and allelic association to GABRB3 (rs8024564, p=0.005; rs8025575, p=0.02) and GABRA5 (rs35399885, p=0.05). Genotyping of an independent Sardinian PD trio sample also supported association in the region, again with a parent-of-origin effect. These findings provide genetic evidence for the involvement of the genes GABRB3 and GABRA5 in the susceptibility to PD.


Assuntos
Transtorno de Pânico/genética , Receptores de GABA-A/genética , Alelos , Linhagem Celular , Grupo com Ancestrais do Continente Europeu/genética , Família , Expressão Gênica , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Itália , Linfócitos/metabolismo , Repetições de Microssatélites , Mutação , Polimorfismo de Nucleotídeo Único , Receptores de GABA-A/metabolismo , Estados Unidos
10.
Biol Psychiatry ; 76(7): 536-41, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24529801

RESUMO

BACKGROUND: While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD). METHODS: We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial. RESULTS: CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100-200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction. CONCLUSIONS: Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.


Assuntos
Variações do Número de Cópias de DNA , Transtorno Depressivo Maior/genética , Transtorno Depressivo Resistente a Tratamento/genética , Citoesqueleto de Actina/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino
11.
Innov Clin Neurosci ; 10(9-10): 15-22, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24307977

RESUMO

OBJECTIVE: To assess the influence of genetic and environmental risk factors upon postpartum depression. DESIGN: Case-control, prospective study. SETTING: The University of California at San Francisco Obstetric and Gynecology Clinic. PARTICIPANTS: Mothers screened for postpartum depression six weeks after delivery with the Edinburgh Postnatal Depression Scale and recruited as cases and controls. MEASUREMENTS: Eligible subjects completed a series of assessments and a structured clinical interview to confirm diagnosis of depression. Deoxyribonucleic acid was obtained for genotyping of 81 single nucleotide polymorphisms in 12 genes hypothesized to be postpartum depression-related. RESULTS: Twenty-four cases and 24 controls were eligible for analysis. Three single necleotide polymorphisms in the serotonin 2A receptor (HTR2A) gene were associated with postpartum depression. The strongest association at a functional promoter polymorphism (rs6311), a functional promoter single nucleotide polymorphisms (p=0.002, odds ratio 0.25, 95% confidence interval:0.10-0.63), was a finding robust to population stratification. Gene-wide association was significant for HTR2A (permuted p=0.008), but not when corrected for all 12 genes. Analysis of demographic and psychosocial risk factors identified distressed relationship, unplanned pregnancy, and a previous history of depression as significant predictive variables (p≤0.05). CONCLUSIONS: This pilot data suggests deoxyribonucleic acid variations in HTR2A may be associated with postpartum depression. Psychosocial variables were also identified as risk factors. The relative influence of these variables on the manifestation of postpartum depression is yet to be determined.

12.
J Psychiatr Res ; 47(9): 1157-65, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23726668

RESUMO

Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short-chain family member 3 gene (ACSS3, p-value=4.5×10(-6), odds ratio=0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p=0.008, OR=1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p=2.11×10(-7)), which resides in chondroitin sulfate N-acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long-term potentiation (FDR=.02). Results suggest novel genetic associations to sustained response.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Ensaios Clínicos como Assunto , Intervalos de Confiança , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Razão de Chances
13.
Neurosci Lett ; 547: 1-5, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23643995

RESUMO

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder, especially in combat veterans. Existing functional neuroimaging studies have provided important insights into the neural mechanisms of PTSD using various experimental paradigms involving trauma recollection or other forms of emotion provocation. However it is not clear whether the abnormal brain activity is specific to the mental processes related to the experimental tasks or reflects general patterns across different brain states. Thus, studying intrinsic spontaneous brain activity without the influence of external tasks may provide valuable alternative perspectives to further understand the neural characteristics of PTSD. The present study evaluated the magnitudes of spontaneous brain activity of male US veterans with or without PTSD, with the two groups matched on age, gender, and ethnicity. Amplitudes of low frequency fluctuation (ALFF), a data driven analysis method, were calculated on each voxel of the resting state fMRI data to measure the magnitudes of spontaneous brain activity. Results revealed that PTSD subjects showed increased spontaneous activity in the amygdala, ventral anterior cingulate cortex, insula, and orbital frontal cortex, as well as decreased spontaneous activity in the precuneus, dorsal lateral prefrontal cortex and thalamus. Within the PTSD group, larger magnitudes of spontaneous activity in the thalamus, precuneus and dorsal lateral prefrontal cortex were associated with lower re-experiencing symptoms. Comparing our results with previous functional neuroimaging findings, increased activity of the amygdala and anterior insula and decreased activity of the thalamus are consistent patterns across emotion provocation states and the resting state.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiopatologia , Distúrbios de Guerra/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Campanha Afegã de 2001- , Humanos , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Veteranos/psicologia , Adulto Jovem
14.
Philos Trans R Soc Lond B Biol Sci ; 368(1615): 20120129, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23440463

RESUMO

The familial nature of major depressive disorder (MDD) is now well recognized. We followed children and grandchildren of probands with and without MDD to examine transmission of depression over generations, and to identify early vulnerability markers prior to the onset of disease. The study now includes three generations and five completed assessment waves spanning 25 years, with a sixth wave underway. Beginning with the fourth wave, we collected measures of brain structure (magnetic resonance imaging, MRI) and physiology (electroencephalography, EEG) and DNA in order to examine at a biological level why the offspring of depressed parents were at higher risk. In this paper, we provide an overview of the study design, the main findings, including new data, and the role of the high-risk design in translational research. We demonstrate that offspring of depressed parents ('high-risk'), when compared with those of non-depressed parents ('low-risk'), were at increased risk for depressive and anxiety disorders, with anxiety appearing earlier and being a predisposing factor for MDD. Offspring with two generations previously affected were at greatest risk. Thinning of the cortical mantle (MRI) and reduced resting-state activity (EEG) within the right parieto-temporal hemisphere differentiated high- from low-risk offspring, regardless of whether the offspring had MDD, suggesting that these measures might serve as familial trait markers for depression and related syndromes. The high- and low-risk offspring also differed by serotonin transporter promoter length polymorphism genotypes, even though the same genotypes were not associated with the presence of MDD. The high-risk epidemiological design appears to be a particularly valuable asset in translational research as it allows targeting of biological processes that emerge prior to the onset of disease, and identifies individuals at high risk for the disorder who may carry the trait or marker but not yet be affected.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Predisposição Genética para Doença , Polimorfismo Genético , Pesquisa Médica Translacional/métodos , Adolescente , Adulto , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Genótipo , Humanos , Lactente , Estudos Longitudinais , Masculino , Linhagem , Regiões Promotoras Genéticas , Estudos Prospectivos , Radiografia , Fatores de Risco , Serotonina/genética , Serotonina/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
15.
Eur Neuropsychopharmacol ; 23(7): 653-62, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23026132

RESUMO

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Depressão/genética , Resistência a Medicamentos/genética , Leptina/sangue , Leptina/genética , Cognição/efeitos dos fármacos , Bases de Dados Genéticas , Depressão/sangue , Depressão/psicologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Leptina/biossíntese , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Resultado do Tratamento
16.
Mol Psychiatry ; 18(4): 497-511, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22472876

RESUMO

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Transtorno Bipolar/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
17.
Neuropharmacology ; 64: 264-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22992330

RESUMO

Intensive computerized auditory training results in improved cognition for schizophrenia patients, but participants show variation in their cognitive gains and the biological factors that affect the response to training are unknown. Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function. Here we asked if functional variation in this gene has an impact on the response of schizophrenia patients to cognitive training. We genotyped 48 schizophrenia patients who completed 50 h of computerized cognitive training and analyzed the association between DNA variants in the COMT gene and the improvement in global cognition. Although conventional analyses did not reveal any significant associations, a set-based analysis examining the aggregate effect of common variation in the COMT gene (42 SNPs) suggested association with improvement in global cognition. Eight SNPs, mostly located in the 3' end of the COMT gene, were nominally associated with improvement in cognition. These data suggest that genotype influences the response to intensive cognitive training in schizophrenia, and may indicate that cognitive training regimens need to be personalized to the underlying biosignatures of each individual patient. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Assuntos
Catecol O-Metiltransferase/genética , Transtornos Cognitivos/prevenção & controle , Terapia Cognitivo-Comportamental , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Esquizofrenia/terapia , Adulto , Catecol O-Metiltransferase/metabolismo , Cognição , Transtornos Cognitivos/etiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Estudos de Associação Genética , Humanos , Masculino , Memória de Curto Prazo , Pessoa de Meia-Idade , Plasticidade Neuronal , Medicina de Precisão , São Francisco , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Terapia Assistida por Computador , Aprendizagem Verbal , Adulto Jovem
18.
PLoS Genet ; 8(9): e1002898, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23028339

RESUMO

Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09 × 10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.


Assuntos
Proteínas de Transporte/genética , Doenças Cocleares/genética , Proteínas de Ligação a DNA/genética , Surdez , Endopeptidases/genética , Envelhecimento/genética , Animais , Mapeamento Cromossômico , Cóclea/crescimento & desenvolvimento , Cóclea/patologia , Surdez/genética , Surdez/veterinária , Cães , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases , Proteases Específicas de Ubiquitina
19.
PLoS One ; 7(9): e46315, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23029476

RESUMO

BACKGROUND: Suicide is one of the top ten leading causes of death in North America and represents a major public health burden, particularly for people with Major Depressive disorder (MD). Many studies have suggested that suicidal behavior runs in families, however, identification of genomic loci that drive this efffect remain to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using subjects collected as part of STAR D, we genotyped 189 subjects with MD with history of a suicide attempt and 1073 subjects with Major Depressive disorder that had never attempted suicide. Copy Number Variants (CNVs) were called in Birdsuite and analyzed in PLINK. We found a set of CNVs present in the suicide attempter group that were not present in in the non-attempter group including in SNTG2 and MACROD2 - two brain expressed genes previously linked to psychopathology; however, these results failed to reach genome-wide signifigance. CONCLUSIONS: These data suggest potential CNVs to be investigated further in relation to suicide attempts in MD using large sample sizes.


Assuntos
Encéfalo/metabolismo , Variações do Número de Cópias de DNA , Transtorno Depressivo Maior/genética , Tentativa de Suicídio/psicologia , Encéfalo/fisiopatologia , Estudos de Coortes , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Cadeias de Markov , Glicoproteínas de Membrana , Proteínas de Membrana/genética , Proteínas Musculares/genética , América do Norte , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco
20.
Psychiatr Genet ; 22(6): 271-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23018769

RESUMO

BACKGROUND: We have previously described a subtype of panic disorder (PD) that we termed 'bladder syndrome', characterized by urological and bladder symptoms (and possibly interstitial cystitis) in the patients and/or their family members and confirmed the validity of this subset in family linkage and association analysis. In this study, we determine (a) whether 20 single-nucleotide polymorphisms (SNPs) reported in the literature can be replicated in a new PD dataset and (b) whether dividing the sample into those with and without the 'bladder syndrome' can help to resolve the genetic heterogeneity within this new sample. METHODS: We selected 20 putative associated SNPs from the literature, taken from studies published since 2004. We tested these SNPs for association in a sample of 351 PD patients and 552 controls, and then divided them into subgroups of 92 patients from bladder families and 259 from nonbladder families. RESULTS: (a) When analyzed in all PD patients, none of the 20 SNPs appeared to be replicated (except for SLC6A4 from our previous study, but in a sample that overlaps substantially with that in our previous report). (b) However, some intriguing findings emerged when we separated bladder from nonbladder families: SLC6A4, reported by us previously, yielded stronger evidence than before (P=0.0018) when examined only in nonbladder families, and in contrast, is not statistically significant in bladder families. Two other markers yielded nominally significant results in bladder families - rs5751876 in ADORA2A (P=0.046) and rs12579350 in TMEM16B (P=0.035) - but were not significant in nonbladder families. (c) Two markers had noticeably lower P-values when we differentiated the women and analyzed them separately - rs12579350 in TMEM16B (P-value decreased from 0.035, as above, to 0.00055) and a different SNP in ADORA2A, rs4822492 (P-value decreases from 0.07 to 0.028). SIGNIFICANCE: Our results indicate that most of the 20 reported associations do not hold up when PD is analyzed as one group. However, our findings provide further evidence that PD with bladder symptoms may be genetically different from PD without bladder. We suggest that it is worth pursuing SLC6A4 in nonbladder PD, and ADORA2A and TMEM16B in bladder PD. Also, the possibility of a male-female difference in PD is worth pursuing. We also briefly discuss issues of replication and multiple tests.


Assuntos
Ansiedade/genética , Transtorno de Pânico/genética , Bexiga Urinária/fisiopatologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Transtorno de Pânico/complicações , Polimorfismo de Nucleotídeo Único , Controle de Qualidade
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