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1.
Biol Psychiatry ; 2019 Aug 05.
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.

2.
J Clin Psychiatry ; 80(4)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31318184

RESUMO

BACKGROUND: Suicidal ideation is a frequent and difficult-to-treat clinical challenge among patients with major depressive disorder (MDD). However, little is known regarding the differential development during antidepressant treatment and whether some patients may suffer from persistent suicidal ideation. METHODS: Among 811 patients with Schedules for Clinical Assessment in Neuropsychiatry (SCAN)-verified MDD from 2004-2007 assessed weekly for 12 weeks of escitalopram or nortriptyline antidepressant treatment, we applied item response theory to integrate a suicidality score based on 3 rating scales. We performed latent growth mixture modeling analysis to empirically identify trajectories. Multinomial logistic regression analyses estimated associations with potential predictors. RESULTS: We identified 5 distinct classes of suicidal ideation. The Persistent-low class (53.7%) showed no suicidal ideation whereas the Persistent-high class (9.8%) had high suicidal ideation throughout 12 weeks. Two classes showed a fluctuating course: the Fluctuating class (5.2%) ended at a low level of suicidal ideation, whereas the Slow-response-relapse class (4.8%) initially responded slowly but then experienced a large increase to a high level of suicidal ideation after 12 weeks. The Fast-response class (26.5%) had a high baseline severity similar to the Persistent-high class but responded quickly within a few weeks and remained at a low level. Previous suicide attempts and higher mood symptom severity were associated with worse suicidal ideation trajectories, whereas living with a partner showed a trend toward better response. CONCLUSION: Approximately 1 of 5 patients with MDD showed high or fluctuating suicidal ideation despite antidepressant treatment. Studies should investigate whether suicidal ideation may persist for longer periods and more targeted treatment possibilities. TRIAL REGISTRATION: ISRCTN​​ identifier: ISRCTN03693000​​​​.

3.
Acta Neuropsychiatr ; 31(4): 186-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31106715

RESUMO

OBJECTIVE: Depression is a disorder caused by genetics and environmental factors. The aim of this study was to perform a review investigating the interaction between genetic variations located in genes involved in hypothalamus-pituitary-adrenal axis (HPA-axis) and stressful life events (SLEs) in depression. METHODS: In this systematic review, we selected articles investigating the interaction between genes involved in the HPA-axis, such as Arginine Vasopressin (AVP), Angiotensin Converting Enzyme (ACE), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2), and SLE. The literature search was conducted using the Pubmed, Embase, and PsychINFO databases in adherence with the PRISMA guidelines. RESULTS: The search yielded 48 potentially relevant studies, of which 40 were excluded following screening. Eight studies were included in the final review. A total of 97 single nucleotide polymorphisms (SNPs) were examined in the eight included studies. The most prevalent gene was FKBP5, and the best studied polymorphism was FKBP5:rs1360780. Two of the five studies reported significant gene-environment (G × E) interactions between rs1360780 and SLE. Overall, four studies reported significant G × E interactions between FKBP5, CRH, or CRHR1 and SLE, respectively. No significant G × E interactions were found for the remaining genes. CONCLUSIONS: Our results suggest that genetic variation in three genes in the HPA-axis possibly moderate the effects of SLEs in depression.

4.
Biol Psychiatry ; 85(12): 1065-1073, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31003785

RESUMO

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. METHODS: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. RESULTS: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. CONCLUSIONS: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.

5.
Br J Psychiatry ; 215(2): 494-501, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30698114

RESUMO

BACKGROUND: For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).AimsTo compare the switch between the TCA nortriptyline and the SSRI escitalopram. METHOD: Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery-Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting ß-coefficients with 95% CIs. RESULTS: Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, ß = -0.38, 95% CI -0.51 to -0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, ß = -0.34, 95% CI -0.41 to -0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions. CONCLUSIONS: These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.Declarations of interestK.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.

6.
Nat Genet ; 50(5): 668-681, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29700475

RESUMO

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

7.
Cerebrovasc Dis ; 45(3-4): 187-192, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614501

RESUMO

INTRODUCTION: Serotonin is known as a neurotransmitter; however, it also plays an important role in platelet aggregation as it is released upon platelet activation. The serotonin transporter (SERT) is responsible for the uptake of serotonin into platelets. Functional polymorphisms in the SERT gene may influence platelet activity, as they result in different levels of transporters and thereby different levels of serotonin in platelets. SERT gene polymorphisms have thus been associated with the risk of myocardial infarction. A similar association may exist between SERT gene polymorphisms and stroke. However, to our knowledge, this potential association has not previously been studied. We therefore aimed to investigate the association between polymorphisms in the SERT gene and the risk of ischemic stroke/transitory ischemic attack (TIA). MATERIALS AND METHODS: We conducted a case-control study including 834 consecutively admitted first-ever Caucasian ischemic stroke patients/TIA from Aarhus University Hospital, Denmark and 571 healthy controls. The control group comprised a sample from the Danish working population, who were all employees in the public sector in the Central Denmark Region. Two polymorphisms, the length variation (short = S/long = L) in the serotonin-transporter-linked polymorphic region and a single-nucleotide (A/G) polymorphism (rs25531) were studied. The genotypes were grouped according to the functional activity: SS, SLG and LGLG (low expression), SLA, LGLA (medium expression), and LALA (high expression). Data were analyzed using logistic regression and results presented as OR with 95% CI. RESULTS: The high-expression genotype was associated with a lower risk of ischemic stroke/TIA when compared to both the medium expression genotype (OR 0.72, 95% CI 0.56-0.93) and the low-expression genotype (OR 0.75, 95% CI 0.55-1.01) as well as the combination of the low and medium expression genotypes (OR 0.73, 95% CI 0.58-0.93). The lower OR estimates associated with the high-expression genotype were consistent across all stroke subtypes, although not statistically significant. The results remained virtually unchanged, although not reaching statistical significance, when adjusting for age and gender. CONCLUSION: The presence of the high expression SERT genotype (LALA) may be associated with a lower risk of ischemic stroke/TIA. This is, to our knowledge, the first study examining the SERT gene polymorphisms and the risk of stroke. The present results raise interesting considerations for future personalized medicine potential, and we argue that further larger-scale studies with sufficient power to study subgroups according to stroke etiology and stroke-onset age are needed.

8.
J Affect Disord ; 232: 260-267, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29499509

RESUMO

BACKGROUND: Studies of individual biomarkers for depression have shown insufficient sensitivity and specificity for clinical use, and most likely combinations of biomarkers may provide a better signature. The sorting-related receptor with A-type repeats (SorLA) is a well-studied pathogenic factor for Alzheimer's. SorLA belongs to the Vps10p domain receptor family, which also encompasses sortilin and SorCS1-3. All family members have been implicated in neurological and mental disorders. Notably, the SORCS3 gene is genome-wide significantly associated with depression and serum protein levels of sortilin are reduced in depressed individuals. SorLA regulates the activity of neurotrophic factors and cytokines and we hence speculated that SorLA might be implicated in depression. METHODS: Serum SorLA levels were measured in two well-defined clinical samples using ELISA. Generalized linear models were used in the statistical analyses. RESULTS: We identified a multivariate model to discriminate depressed individuals from healthy controls. Interestingly, the model consisted of serum SorLA levels and additional four predictors: previous depressive episode, stressful life events, serum levels of sortilin and VEGF. However, as an isolated factor, we observed no significant difference in SorLA levels between 140 depressed individuals and 140 healthy controls. Nevertheless, we observed a significant increase in SorLA levels following 12 weeks of treatment with nortriptyline, but not escitalopram. LIMITATIONS: The number of biomarkers included in the multivariate model for depression and lack of replication limit our study. CONCLUSIONS: Our results suggest SorLA as one of five factors that in combination may support the depression diagnosis, but not as an individual biomarker for depression or treatment response.


Assuntos
Transtorno Depressivo/sangue , Transtorno Depressivo/genética , Proteínas Relacionadas a Receptor de LDL/sangue , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/sangue , Proteínas de Membrana Transportadoras/genética , Proteínas Adaptadoras de Transporte Vesicular , Adulto , Animais , Dinamarca , Feminino , Humanos , Masculino , Transporte Proteico
9.
Brain Behav Immun ; 62: 344-350, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28257825

RESUMO

INTRODUCTION: Population-based studies have associated inflammation, particularly higher C-reactive protein (CRP), with depressive severity, but clinical trials in major depressive disorder were rather non-specific without examining the role of gender. We aimed to investigate the association between CRP and overall depression severity including specific depressive symptoms and to examine potential gender differences. METHODS: We included 231 individuals with major depressive disorder from the Genome-Based Therapeutics Drugs for Depression (GENDEP) study. At baseline, we assessed high-sensitivity CRP levels and psychopathology with the Montgomery Aasberg Depression Rating Scale (MADRS). We performed linear regression analyses to investigate the association between baseline CRP levels with overall MADRS severity and specific symptoms at baseline and adjusted for age, gender, anti-inflammatory and psychotropic drug treatment, body mass index, smoking, inflammatory diseases, and recruitment center. RESULTS: Higher CRP levels were significantly associated with greater overall MADRS symptom severity (p=0.02), which was significant among women (p=0.02) but not among men (p=0.68). Among women, higher CRP was associated with increased severity on observed mood, cognitive symptoms, interest-activity, and suicidality, but we found no significant associations among men. Interaction analyses showed no significant gender differences on the overall MADRS score or specific symptoms. DISCUSSION: Our results support the sickness syndrome theory suggesting that chronic low-grade inflammation may be associated with a subtype of depression. The potential gender differences in psychopathology may be explained by biological and/or psychosocial factors, e.g. differential modulation of immune responses by sex hormones. Clinical studies should investigate symptom-specific and/or gender-specific treatment guided by peripheral inflammatory markers.


Assuntos
Proteína C-Reativa/análise , Depressão/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Adulto , Biomarcadores/sangue , Depressão/sangue , Transtorno Depressivo Maior/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais
10.
Artigo em Inglês | MEDLINE | ID: mdl-28159590

RESUMO

BACKGROUND: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait. METHODS: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756). RESULTS: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results. DISCUSSION: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Herança Multifatorial/genética , Farmacogenética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fatores de Risco , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
11.
Psychiatr Genet ; 27(3): 89-95, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28225367

RESUMO

OBJECTIVES: The identification of peripheral biomarkers for bipolar disorder is of great importance and has the potential to improve diagnosis, treatment and prognosis. Recent studies have reported lower plasma progranulin levels in bipolar individuals compared with controls and association with single nucleotide polymorphisms (SNPs) within the progranulin gene (GRN). In the present study, we investigated the effect of GRN and sortilin (SORT1) gene variation on serum progranulin levels in bipolar individuals and controls. MATERIALS AND METHODS: In a Danish cohort of individuals with bipolar disorder and controls, we analysed the serum progranulin level (nbipolar=80, ncontrols=76) and five SNPs located within GRN and two SNPs near the SORT1 gene encoding sortilin, a progranulin scavenger receptor known to affect circulating progranulin levels (nbipolar=166, ncontrols=186). RESULTS: We observed no significant difference in the serum progranulin level between cases and controls and none of the analysed SNPs located within GRN or close to SORT1 were associated with bipolar disorder. Crude and adjusted (adjusted for case-control status, sex and age) linear regression analyses showed no effect of any SNPs on the serum progranulin level. However, we observed that the mean serum progranulin level in cases and controls is affected differently depending on the genotypes of two SNPs within GRN (rs2879096 and rs4792938). LIMITATION: The sample size is relatively small and detailed information on medication and polarity of the disorder is not available. No correction for multiple testing was performed. CONCLUSION: Our study suggests that the potential of progranulin as a biomarker for bipolar disorder is genotype dependent.


Assuntos
Transtorno Bipolar/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Progranulinas
12.
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
13.
Psychiatr Genet ; 26(6): 287-292, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27610895

RESUMO

Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD.


Assuntos
Cromossomos Humanos Par 19/genética , Transtorno de Pânico/genética , Adulto , Cromossomos Humanos Par 19/metabolismo , Estudos de Coortes , Dinamarca , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alemanha , Humanos , MAP Quinase Quinase 7/genética , Masculino , Proteínas de Membrana/genética , Transtorno de Pânico/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
14.
Am J Med Genet B Neuropsychiatr Genet ; 171(8): 1013-1022, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27255576

RESUMO

The demographic history of the isolated population of the Faroe Islands may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for panic disorder (PD). PD is a common mental disorder, characterized by recurring and unprovoked panic attacks, and genetic factors have been estimated to explain around 40% of the risk. In this study the potential enrichment of PD risk variants was explored based on whole-exome sequencing of 54 patients with PD and 211 control individuals from the Faroese population. No genome-wide significant associations were found, however several single variants and genes showed strong association with PD, where DGKH was found to be the strongest PD associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. Additionally, we found an enrichment of PD risk variants in the Faroese population; variants with otherwise low frequency in more outbreed European populations. © 2016 Wiley Periodicals, Inc.


Assuntos
Diacilglicerol Quinase/genética , Transtorno de Pânico/genética , Adulto , Dinamarca , Diacilglicerol Quinase/metabolismo , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Masculino , Transtorno de Pânico/psicologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
15.
J Affect Disord ; 183: 287-94, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26047306

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF) have been suggested to play a role in the pathophysiology of depression. The neurotrophic model of depression hypothesises that the serum level of e.g. BDNF is decreased during depression and increased in response to treatment. The aim of the present study was to investigate BDNF and VEGF as potential predictors of response to antidepressant treatment. METHODS: We investigated the longitudinal associations between depression scores and serum levels of these neurotrophic factors during antidepressant treatment in 90 individuals with depression of at least moderate severity. Serum levels were measured at baseline and after 8 and 12 weeks of treatment with nortriptyline or escitalopram. RESULTS: No baseline or longitudinal correlations between depression scores and serum levels of BDNF and VEGF were found, and the baseline serum levels did not predict the MADRS depression score after 12 weeks of treatment or the improvement in depression scores. Interestingly, we observed a significant baseline and longitudinal correlation between serum levels of BDNF and VEGF. The two classes of antidepressant treatment did not affect the results differently. LIMITATIONS: Information on potential factors influencing the serum levels is missing. CONCLUSION: Our results do not support the neurotrophic model of depression, since a significant decrease in serum BDNF and VEGF levels after 12 weeks of antidepressant treatment was observed. Our study encourages future studies with large sample sizes, more observations and a longer follow-up period.


Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/sangue , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Citalopram/uso terapêutico , Feminino , Humanos , Masculino , Nortriptilina/uso terapêutico , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
16.
PLoS Genet ; 10(7): e1004488, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25058410

RESUMO

We carried out an admixture analysis of a sample comprising 1,019 individuals from all the provinces of Cuba. We used a panel of 128 autosomal Ancestry Informative Markers (AIMs) to estimate the admixture proportions. We also characterized a number of haplogroup diagnostic markers in the mtDNA and Y-chromosome in order to evaluate admixture using uniparental markers. Finally, we analyzed the association of 16 single nucleotide polymorphisms (SNPs) with quantitative estimates of skin pigmentation. In the total sample, the average European, African and Native American contributions as estimated from autosomal AIMs were 72%, 20% and 8%, respectively. The Eastern provinces of Cuba showed relatively higher African and Native American contributions than the Western provinces. In particular, the highest proportion of African ancestry was observed in the provinces of Guantánamo (40%) and Santiago de Cuba (39%), and the highest proportion of Native American ancestry in Granma (15%), Holguín (12%) and Las Tunas (12%). We found evidence of substantial population stratification in the current Cuban population, emphasizing the need to control for the effects of population stratification in association studies including individuals from Cuba. The results of the analyses of uniparental markers were concordant with those observed in the autosomes. These geographic patterns in admixture proportions are fully consistent with historical and archaeological information. Additionally, we identified a sex-biased pattern in the process of gene flow, with a substantially higher European contribution from the paternal side, and higher Native American and African contributions from the maternal side. This sex-biased contribution was particularly evident for Native American ancestry. Finally, we observed that SNPs located in the genes SLC24A5 and SLC45A2 are strongly associated with melanin levels in the sample.


Assuntos
Fluxo Gênico/genética , Genética Populacional , Haplótipos/genética , Pigmentação/genética , Grupo com Ancestrais do Continente Africano/genética , Cromossomos Humanos Y/genética , Cuba , DNA Mitocondrial/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Humanos , Índios Norte-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética
17.
Int J Neuropsychopharmacol ; 17(9): 1409-17, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24636631

RESUMO

Recent studies suggest that the angiogenic cytokine vascular endothelial growth factor (VEGF) is involved in the pathogenesis of depression. However, only a few studies have investigated serum VEGF levels in individuals with depression, or the possible association between genetic variants within the VEGF gene and depression. The purpose of the present study was to investigate differences between serum VEGF levels in individuals with depression vs. control individuals, and associations between genetic markers located within VEGF and depression. In addition, determinants of the serum VEGF levels were identified. One-hundred and fifty-five depressed subjects and 280 controls were included in the study. All individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Eleven single nucleotide polymorphisms were successfully analysed. VEGF levels were measured in serum by immunoassay and independent determinants of the serum VEGF level were assessed by generalized linear models.The main findings were that depression, severity of depression, previous depressive episodes, age and body mass index (BMI) were associated with higher serum VEGF levels. The genetic marker rs10434 was significantly associated with depression after correction for multiple testing, but not with the serum VEGF level. Our final model included depression and BMI as predictors of serum VEGF levels. Our study suggests a role for circulating serum VEGF in depression. Furthermore, our data also demonstrate that other factors than a diagnosis of depression influence the serum VEGF level. The importance of these factors should be emphasized when studies are compared.


Assuntos
Índice de Massa Corporal , Depressão/sangue , Depressão/genética , Polimorfismo de Nucleotídeo Único/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não Paramétricas
18.
Psychiatr Genet ; 24(1): 37-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24362369

RESUMO

We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previously reported candidate region for PD. Three single nucleotide polymorphisms (rs887231, rs887230 and rs4795942) located upstream and within TMEM132E showed a nominal significant association with PD primarily in the Danish cohort. No nominal significant associations were observed between TMEM98 and PD. Our data indicate that TMEM132E might contribute moderately towards the risk of developing PD.


Assuntos
Proteínas de Membrana/genética , Transtorno de Pânico/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 17 , Humanos , Polimorfismo de Nucleotídeo Único
19.
Psychiatr Genet ; 23(5): 217-21, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23969988

RESUMO

A potential approach for identification of candidate genes for depression is characterization of chromosomal rearrangements. Through analysis of a chromosome translocation in an individual with recurrent depression, we identified a potential candidate gene: the norepinephrine transporter (NET; SLC6A2 for solute carrier 6 family member 2). The gene is responsible for the reuptake of norepinephrine and dopamine into presynaptic nerve terminals and the norepinephrine system appears to play an important role in depression. We therefore analyzed genetic variants within SLC6A2 for association with depression in 408 affected and 559 control individuals from Denmark. After quality control of the genotypes, 31 of 45 single nucleotide polymorphisms (SNPs) were left for analyses. One SNP showed a nominal association with depression but did not survive correction for multiple testing. The results from our study do not suggest SLC6A2 as a susceptibility gene for depression in the Danish population.


Assuntos
Depressão/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Adulto , Quebra Cromossômica , Cromossomos Humanos Par 16/genética , Feminino , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Translocação Genética
20.
J Affect Disord ; 148(2-3): 291-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23313272

RESUMO

INTRODUCTION: Strong evidence demonstrates a genetic susceptibility to suicidal behaviour and a relationship between suicide and mental disorders. The aim of this study was to test for association between suicide and five selected genetic variants, which had shown association with suicide in other populations. METHOD: We performed a nationwide case-control study on all suicide cases sent for autopsy in Denmark between the years 2000 and 2007. The study comprised 572 cases and 1049 controls and is one of the largest genetic studies in completed suicide to date. The analysed markers were located within the Serotonin Transporter (SLC6A4), Monoamine Oxidase-A (MAOA) and the Tryptophan Hydroxylase I and II (TPH1 and TPH2) genes. RESULTS: None of the genetic markers within SLC6A4, MAOA, TPH1 and TPH2 were significantly associated with completed suicide or suicide method in the basic association tests. Exploratory interaction test showed that the minor allele of rs1800532 in TPH1 has a protective effect for males younger than 35 years and females older than 50 years, whereas for the oldest male subjects, it tended to be a risk factor. We also observed a significant interaction between age-group and the 5-HTTLPR genotype (with and without rs25531) in SLC6A4. The long allele or high expression allele tends to have a protective effect in the middle age-group. LIMITATION: We only analysed a limited number of genetic variants. CONCLUSION: None of the analysed variants are strong risk factors. To reveal a better understanding of the genes involved in suicide, we suggest future studies should include both genetic and non-genetic factors.


Assuntos
Monoaminoxidase/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Suicídio/estatística & dados numéricos , Triptofano Hidroxilase/genética , Adulto , Fatores Etários , Idoso , Alelos , Estudos de Casos e Controles , Dinamarca , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
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