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1.
Artigo em Inglês | MEDLINE | ID: mdl-33684623

RESUMO

BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if so, how these effects could contribute to the disease course of MDD. METHODS: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic MDD patients and 539 healthy controls. RESULTS: Polygenic risk score for T2D across MDD patients and healthy controls was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this FA variation may mediate the association between PGS and cognitive performance. CONCLUSIONS: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in MDD patients and healthy controls, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.

2.
Age Ageing ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33352580

RESUMO

OBJECTIVES: The purpose of this paper is to investigate the utilisation of general practice Medicare Benefit Schedule (MBS) services aligned to Comprehensive Geriatric Assessment (CGA) within 6 months of an aged care eligibility assessment and its effects on mortality and transition to permanent residential aged care (PRAC). DESIGN: Retrospective cohort study from the Historical Cohort of the Registry of Senior Australians. SETTING: Community. PARTICIPANTS: In total, 69,171 Individuals (aged 75+) receiving home care packages (HCPs) between 2011 and 2015. OUTCOME MEASURES: Mortality and transition to PRAC. RESULTS: The claims for a management plan with team care arrangement (TCA) within 3 months of the health assessment (i.e. CGA) was present in 5% and associated with 14% lower mortality (adjusted hazard ratio [aHR], 95%CI = 0.86, 0.80-0.93) compared to no claims, lower than that seen with partial CGA which was either health assessment claims only 7.0% (aHR, 95%CI = 0.93, 0.89-0.97) or management plan coupled with TCA claims only 9.0% (aHR, 95%CI = 0.91, 0.89-0.97). This pattern was seen in those frailer but not in those where the frailty index score was <0.21. Claims for management plans coupled with TCAs alone were associated with a 10% lower transition to PRAC (asHR, 95%CI = 0.90, 0.85-0.96) in those with FI score < 0.21 while this estimate was not significant in individuals with FI score ≥ 0.21. CONCLUSION: It appears the conduct of a combination of interventions considered to be components of the CGA by GPs was associated with a lower risk of mortality that no claims or partial conduct of CGA.

3.
Pharmacopsychiatry ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33147643

RESUMO

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

4.
Med J Aust ; 213(7): 321-326, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32776351

RESUMO

OBJECTIVES: To develop and validate a frailty index, derived from aged care eligibility assessment data. DESIGN: Retrospective cohort study; analysis of the historical national cohort of the Registry of Senior Australians (ROSA). PARTICIPANTS: 903 996 non-Indigenous Australians aged 65 years or more, living in the community and assessed for subsidised aged care eligibility during 2003-2013. MAIN OUTCOME MEASURES: 44-item frailty index; summary statistics for frailty index score distribution; predictive validity with respect to mortality and entry into permanent residential aged care during the five years after assessment. RESULTS: The mean frailty index score during 2003-2013 was 0.20 (SD, 0.07; range, 0-0.41); the proportion of assessed older people with scores exceeding 0.20 increased from 32.1% in 2003-2005 to 75.0% in 2012-2013. The risks of death and entry into permanent residential aged care at one, three and five years increased with frailty index score level (at one year, high [over 0.35] v low scores [under 0.05]: hazard ratio for death, 5.99; 95% CI, 5.69-6.31; for entry into permanent residential aged care, 8.70; 95% CI, 8.32-9.11). The predictive validity (area under the receiver operating characteristic curve) of Cox proportional hazard models including age, sex, and frailty index score was 0.64 (95% CI, 0.63-0.64) for death and 0.63 (95% CI, 0.62-0.63) for entry into permanent residential aged care within one year of assessment. CONCLUSIONS: We used Australian aged care eligibility assessment program data to construct and validate a frailty index. It can be employed in aged care research in Australia, but its application to aged care planning requires further investigation.


Assuntos
Idoso Fragilizado/estatística & dados numéricos , Fragilidade/diagnóstico , Avaliação Geriátrica/métodos , Indicadores Básicos de Saúde , Idoso , Idoso de 80 Anos ou mais , Austrália , Feminino , Serviços de Saúde para Idosos , Humanos , Masculino , Valor Preditivo dos Testes , Avaliação de Programas e Projetos de Saúde , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco
5.
Aust N Z J Psychiatry ; 54(12): 1200-1211, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32746615

RESUMO

OBJECTIVE: Mental health disorders are a major health concern in older people and are associated with a higher risk of disability, frailty and early mortality. This study aimed to conduct a contemporary population-based assessment of the prevalence, trends and factors associated with mental health disorders in individuals who are living in permanent residential aged care (PRAC) in Australia. METHODS: A retrospective cross-sectional study was conducted using national data from the Registry of Senior Australians, a national cohort of older Australians who had aged care eligibility assessment and entered PRAC between 2008 and 2016. Stepwise multivariate logistic regression modeling was applied to identify factors associated with mental health disorders. RESULTS: Of 430,862 individuals included in this study, 57.8% had at least one mental health disorder. The prevalence of depression, phobia/anxiety and psychosis were as follows: 46.2% (95% confidence interval = [46.0%, 46.3%]), 14.9% (95% confidence interval = [14.8%, 15.0%]) and 9.7% (95% confidence interval = [9.6%, 9.8%]), respectively. The likelihood of having a mental health disorder was higher for those who were (adjusted odds ratio [95% confidence interval]) relatively younger, specifically for every 10-year increment in age, the odds of having mental health disorders was 44.0% lower (0.56, [0.55, 0.56]); female (1.33 [1.32, 1.35]); having increasing numbers of physical health comorbidities, 6-10 (1.26 [1.24, 1.29]) or 11-15 (1.48 [1.45, 1.51]) or more than 15 (1.64 [1.58, 1.71]) compared to people having less than five comorbidities; having limitations related to health care tasks (1.05 [1.04, 1.07]), meals (1.04 [1.02, 1.05]) or social and community participation (1.10 [1.08, 1.12]). CONCLUSION: The burden of mental health disorders in older Australians living in PRAC was high and individuals with these conditions tend to be younger, with several physical comorbidities and/or functional limitations. Understanding the profile of individuals with mental health disorders at entry into PRAC can be used as evidence for baseline resource allocation for this population and evaluation of future needs of mental health services.

6.
Age Ageing ; 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32614940

RESUMO

OBJECTIVE: (i) to describe the general practitioner utilisation of health assessments, management plans, coordination of team care arrangements and medication review item numbers within 6 months of an aged care eligibility assessment for home care packages (HCP) and (ii) investigate the impact of health assessments on the risk of mortality and entry into permanent residential aged care (PRAC) of individuals accessing HCP. DESIGN AND SETTING: retrospective cohort study utilising data from the Registry of Senior Australians (ROSA) was conducted. SUBJECTS: 75,172 individuals aged ≥75 years who received HCP between 2011 and 2015. OUTCOME MEASURE: for objective 1: the use of comprehensive assessments (Medicare Benefits Schedule (MBS) items 705 or 707), management plans (MBS 721), coordination of team care arrangements (MBS 723), and medication reviews (MBS 900). For objective 2: time to death and entry into PRAC. RESULTS: of the 75,172 individuals, 28.2% (95% confidence interval (CI): 27.8-8.5%) had comprehensive assessments, 36.7% (95% CI: 36.3-37.0%) had management plans, 33.0% (95% CI: 32.7-33.3%) received coordination of team care arrangements and 5.4% (95% CI: 5.2-5.5%) had medication reviews. Individuals with a comprehensive assessment had a 5% lower risk of mortality (adjusted hazard ratio (aHR), 95% CI = 0.95, 0.92-0.98) but 5% higher risk of transition to PRAC (adjusted subdistribution HRs, 95% CI = 1.05, 1.02-1.08) compared to those who did not have these services. CONCLUSION: the utilisation of health assessments was associated with a lower risk of mortality. There is an opportunity for increased use of item numbers in frailer individuals.

7.
Mol Psychiatry ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32203155

RESUMO

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

8.
Australas J Ageing ; 39(3): e382-e392, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31975527

RESUMO

OBJECTIVE: To evaluate the access of approved aged care services and factors associated with accessing these services. METHODS: A retrospective cohort study was conducted (1/7/2003-30/6/2013). The incidence of accessing permanent residential, home and respite care services within one year or transition care within 28 days of approval was evaluated. The association of participants' socio-demographic characteristics, limitations, health conditions and assessment characteristics with service use was evaluated. RESULTS: In 799 750 older Australians, the incidence of accessing approved permanent residential care within one year was 70.9% (95% confidence interval [CI] 70.8%-71.0%), home care 49.5% (95% CI 49.3%-49.7%) and respite 41.8% (95% CI 41.7%-41.9%). The incidence of accessing transition care at 28 days was 78.5% (95% CI 78.2%-78.7%). Aged care seekers', assessments' and assessors' characteristics are associated with service access. CONCLUSION: Monitoring the use of aged care service approvals is necessary for the identification of service access barriers to support evidence-based policy changes.

9.
Mol Psychiatry ; 25(12): 3422-3431, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30185937

RESUMO

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

10.
Mol Psychiatry ; 25(7): 1420-1429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-30626913

RESUMO

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53 ± 0.09 and 0.57 ± 0.05, respectively. From a total of 20 independent genome-wide significant loci, 13 loci replicated of which 8 were novel for depression. These were MUC21 for the broad depression phenotype with self-reported MDD and ZNF804A, MIR3143, PSORS1C2, STK19, SPATA31D1, RTN1 and TCF4 for the broad depression phenotype with schizophrenia. Post-GWAS functional analyses of these loci revealed their potential biological involvement in psychiatric disorders. Our results emphasize the genetic similarities among different psychiatric disorders and indicate that cross-disorder analyses may be the best way forward to accelerate gene finding for depression, or psychiatric disorders in general.

11.
Sci Rep ; 9(1): 12041, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427629

RESUMO

Female reproductive behaviours have important implications for evolutionary fitness and health of offspring. Here we used the second release of UK Biobank data (N = 220,685) to evaluate the association between five female reproductive traits and polygenic risk scores (PRS) projected from genome-wide association study summary statistics of six psychiatric disorders (N = 429,178). We found that the PRS of attention-deficit/hyperactivity disorder (ADHD) were strongly associated with age at first birth (AFB) (genetic correlation of -0.68 ± 0.03), age at first sexual intercourse (AFS) (-0.56 ± 0.03), number of live births (NLB) (0.36 ± 0.04) and age at menopause (-0.27 ± 0.04). There were also robustly significant associations between the PRS of eating disorder (ED) and AFB (0.35 ± 0.06), ED and AFS (0.19 ± 0.06), major depressive disorder (MDD) and AFB (-0.27 ± 0.07), MDD and AFS (-0.27 ± 0.03) and schizophrenia and AFS (-0.10 ± 0.03). These associations were mostly explained by pleiotropic effects and there was little evidence of causal relationships. Our findings can potentially help improve reproductive health in women, hence better child outcomes. Our findings also lend partial support to the evolutionary hypothesis that causal mutations underlying psychiatric disorders have positive effects on reproductive success.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais/etiologia , Característica Quantitativa Herdável , Reprodução , Adolescente , Adulto , Idoso , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Humanos , Masculino , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Herança Multifatorial , Reprodução/genética , Fatores de Risco , Adulto Jovem
12.
Neuropsychopharmacology ; 44(13): 2212-2219, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31284291

RESUMO

Genetic predisposition and brain structural abnormalities have been shown to be involved in the biological underpinnings of anorexia nervosa (AN). Prefrontal brain regions are suggested to contribute through behavioral inhibition mechanisms to body weight. However, it is unknown if and to which extent biological correlates for AN might be present in individuals without clinical AN symptomatology. We therefore investigated the contribution of polygenic load for AN on body weight and prefrontal brain structure in a sample of n = 380 nonclinical individuals. A polygenic score (PGS) reflecting the individual genetic load for the trait of anorexia nervosa was calculated. Structural MRI data were acquired and preprocessed using the cortical parcellation stream of FreeSurfer. We observed a significant PGS × sex interaction effect on body mass index (BMI), which was driven by a negative correlation between PGS and BMI in female participants. Imaging analyses revealed significant interaction effects of sex × PGS on surface area of the lateral orbitofrontal cortex (OFC), the pars orbitalis (PO), the rostral middle frontal gyrus (RMF) and the pars triangularis (PT) of the left frontal cortex. The interaction effects were driven by positive correlations between PGS and prefrontal surface areas in female participants and negative correlations in male participants. We furthermore found sex-specific associations between BMI and left RMF surface area as well as between BMI and left PO and left RMF thickness. Our findings demonstrate a sex-specific association between polygenic load for AN, BMI, and prefrontal brain structure in nonclinical individuals. Hence, this study identifies structural abnormalities associated with polygenic load for AN and BMI in brain regions deeply involved in behavioral inhibition and impulse regulation as candidate brain regions for future research.


Assuntos
Anorexia Nervosa/genética , Anorexia Nervosa/patologia , Herança Multifatorial , Córtex Pré-Frontal/patologia , Caracteres Sexuais , Adolescente , Adulto , Índice de Massa Corporal , Peso Corporal , Feminino , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Sci Rep ; 9(1): 4076, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30858448

RESUMO

Before implementing therapeutic genomic interventions for optimizing health in early life, comprehensive understanding of their effect on several traits across the life course is warranted. Abnorml  birthweight is associated with cardiometabolic disease risk in adulthood; however, the extent of genetic pleiotropy in the association has not been comprehensively investigated. We tested for pleiotropy and enrichment of functional loci between birthweight and 15 cardiometabolic disease traits (CMD). We found significantly abundant genetic pleiotropy (P < 3.3 × 10-3) and enrichment of functional annotations (P < 3.3 × 10-3) in loci influencing both birthweight and CMD. We did not observe consistent effect directions of pleiotropic loci on the traits. A total of 67 genetic loci, of which 65 loci have been reported in previous genome-wide association studies, were associated with both birthweight and CMD at a false discovery rate of 5%. Two novel loci were associated with birthweight and adult coronary artery disease (rs2870463 in CTRB1) and with birthweight and adult waist circumference (rs12704673 in CALCR). Both loci are known to have regulatory effects on expression of nearby genes. In all, our findings revealed pervasive genetic pleiotropy in early growth and adulthood cardiometabolic diseases, implying the need for caution when considering genetic loci as therapeutic targets.


Assuntos
Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Pleiotropia Genética/genética , Predisposição Genética para Doença , Adulto , Doença da Artéria Coronariana/fisiopatologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
14.
Ethiop J Health Sci ; 29(1): 859-868, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30700953

RESUMO

Background: The burden of HIV/AIDS in Ethiopia has not been comprehensively assessed over the last two decades. In this study, we used the 2016 Global Burden of Diseases, Injuries and Risk factors (GBD) data to analyze the incidence, prevalence, mortality and Disability-adjusted Life Years Lost (DALY) rates of Human Immunodeficiency Virus / Acquired Immune Deficiency Syndrome (HIV/AIDS) in Ethiopia over the last 26 years. Methods: The GBD 2016 used a wide range of data source for Ethiopia such as verbal autopsy (VA), surveys, reports of the Federal Ministry of Health and the United Nations (UN) and published scientific articles. The modified United Nations Programme on HIV/AIDS (UNAIDS) Spectrum model was used to estimate the incidence and mortality rates for HIV/AIDS. Results: In 2016, an estimated 36,990 new HIV infections (95% uncertainty interval [UI]: 8775-80262), 670,906 prevalent HIV cases (95% UI: 568,268-798,970) and 19,999 HIV deaths (95% UI: 16426-24412) occurred in Ethiopia. The HIV/AIDS incidence rate peaked in 1995 and declined by 6.3% annually for both sexes with a total reduction of 77% between 1990 and 2016. The annualized HIV/AIDS mortality rate reduction during 1990 to 2016 for both sexes was 0.4%. Conclusions: Ethiopia has achieved the 50% reduction of the incidence rate of HIV/AIDS based on the Millennium Development Goals (MDGs) target. However, the decline in HIV/AIDS mortality rate has been comparatively slow. The country should strengthen the HIV/AIDS detection and treatment programs at community level to achieve its targets during the Sustainable Development Program (SDGs)-era.


Assuntos
Carga Global da Doença/estatística & dados numéricos , Infecções por HIV/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Etiópia/epidemiologia , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto Jovem
15.
J Neural Transm (Vienna) ; 126(1): 35-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30610379

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.


Assuntos
Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/tratamento farmacológico , Obesidade/genética , Avaliação de Resultados em Cuidados de Saúde , Variantes Farmacogenômicos , Inibidores de Captação de Serotonina/farmacologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Comorbidade , Doença da Artéria Coronariana/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Adulto Jovem
16.
Transl Psychiatry ; 8(1): 183, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185780

RESUMO

Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0-10) phenotype (cor = -0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium's mode of action, and could underlie a favourable therapeutic response.


Assuntos
Transtorno Bipolar/genética , Transporte de Elétrons , Redes Reguladoras de Genes , Lítio/uso terapêutico , Mitocôndrias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Fenótipo , Resultado do Tratamento , Adulto Jovem
17.
BMC Med ; 16(1): 70, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29792231

RESUMO

BACKGROUND: Birthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations. METHODS: Genotype data were extracted from phase 3 of the 1000 Genomes Project for 2504 participants from 26 global populations grouped into five super-populations. GRB was calculated in offspring as the weighted sum of the number of birthweight-lowering genetic variants of 59 autosomal single-nucleotide polymorphisms associated with birthweight, and comparisons were made between Europeans and non-Europeans. RESULTS: GRB was significantly higher in Africans (mean difference 3.15; 95% confidence interval 2.64, 3.66), admixed Americans (3.02; 2.34, 3.70), East Asians (2.85; 2.29, 3.41), and South Asians (1.07; 0.49, 1.65) compared to Europeans. Birthweight-lowering genetic variants in Africans and East Asians were enriched for rare and frequency-fixed alleles (P < 0.001). African and Asian populations had the greatest deviation from the expectation of the common disease-common variant hyothesis. Compared to Europeans, the GRB of ancestral alleles was significantly higher and that of derived alleles was significantly lower in non-Europeans (P < 0.001). CONCLUSIONS: The burden of birthweight-lowering genetic variants is higher in Africans and East Asians. This finding is consistent with the high incidence of low birthweight in the two populations. The genetic variants we studied may not be causal and the extent to which they tag the causal variants in non-Europeans is unknown; however, our findings highlight that genetic variations contribute to population differences in birthweight.


Assuntos
Peso ao Nascer/genética , Variação Genética/genética , África , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino
18.
BMC Public Health ; 18(1): 552, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29699588

RESUMO

BACKGROUND: Twelve of the 17 Sustainable Development Goals (SDGs) are related to malnutrition (both under- and overnutrition), other behavioral, and metabolic risk factors. However, comparative evidence on the impact of behavioral and metabolic risk factors on disease burden is limited in sub-Saharan Africa (SSA), including Ethiopia. Using data from the Global Burden of Disease (GBD) Study, we assessed mortality and disability-adjusted life years (DALYs) attributable to child and maternal undernutrition (CMU), dietary risks, metabolic risks and low physical activity for Ethiopia. The results were compared with 14 other Eastern SSA countries. METHODS: Databases from GBD 2015, that consist of data from 1990 to 2015, were used. A comparative risk assessment approach was utilized to estimate the burden of disease attributable to CMU, dietary risks, metabolic risks and low physical activity. Exposure levels of the risk factors were estimated using spatiotemporal Gaussian process regression (ST-GPR) and Bayesian meta-regression models. RESULTS: In 2015, there were 58,783 [95% uncertainty interval (UI): 43,653-76,020] or 8.9% [95% UI: 6.1-12.5] estimated all-cause deaths attributable to CMU, 66,269 [95% UI: 39,367-106,512] or 9.7% [95% UI: 7.4-12.3] to dietary risks, 105,057 [95% UI: 66,167-157,071] or 15.4% [95% UI: 12.8-17.6] to metabolic risks and 5808 [95% UI: 3449-9359] or 0.9% [95% UI: 0.6-1.1] to low physical activity in Ethiopia. While the age-adjusted proportion of all-cause mortality attributable to CMU decreased significantly between 1990 and 2015, it increased from 10.8% [95% UI: 8.8-13.3] to 14.5% [95% UI: 11.7-18.0] for dietary risks and from 17.0% [95% UI: 15.4-18.7] to 24.2% [95% UI: 22.2-26.1] for metabolic risks. In 2015, Ethiopia ranked among the top four countries (of 15 Eastern SSA countries) in terms of mortality and DALYs based on the age-standardized proportion of disease attributable to dietary and metabolic risks. CONCLUSIONS: In Ethiopia, while there was a decline in mortality and DALYs attributable to CMU over the last two and half decades, the burden attributable to dietary and metabolic risks have increased during the same period. Lifestyle and metabolic risks of NCDs require more attention by the primary health care system of the country.


Assuntos
Transtornos da Nutrição Infantil/epidemiologia , Efeitos Psicossociais da Doença , Dieta/normas , Desnutrição/epidemiologia , Doenças Metabólicas/epidemiologia , Doenças não Transmissíveis/epidemiologia , Comportamento Sedentário , Adolescente , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Criança , Pessoas com Deficiência/estatística & dados numéricos , Etiópia/epidemiologia , Feminino , Carga Global da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Adulto Jovem
19.
Front Psychiatry ; 9: 65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559929

RESUMO

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.

20.
Aust N Z J Psychiatry ; 52(5): 483-490, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29325437

RESUMO

OBJECTIVES: Timely and accurate assessments of disease burden are essential for developing effective national health policies. We used the Global Burden of Disease Study 2015 to examine burden due to mental and substance use disorders in Australia. METHODS: For each of the 20 mental and substance use disorders included in Global Burden of Disease Study 2015, systematic reviews of epidemiological data were conducted, and data modelled using a Bayesian meta-regression tool to produce prevalence estimates by age, sex, geography and year. Prevalence for each disorder was then combined with a disorder-specific disability weight to give years lived with disability, as a measure of non-fatal burden. Fatal burden was measured as years of life lost due to premature mortality which were calculated by combining the number of deaths due to a disorder with the life expectancy remaining at the time of death. Disability-adjusted life years were calculated by summing years lived with disability and years of life lost to give a measure of total burden. Uncertainty was calculated around all burden estimates. RESULTS: Mental and substance use disorders were the leading cause of non-fatal burden in Australia in 2015, explaining 24.3% of total years lived with disability, and were the second leading cause of total burden, accounting for 14.6% of total disability-adjusted life years. There was no significant change in the age-standardised disability-adjusted life year rates for mental and substance use disorders from 1990 to 2015. CONCLUSION: Global Burden of Disease Study 2015 found that mental and substance use disorders were leading contributors to disease burden in Australia. Despite several decades of national reform, the burden of mental and substance use disorders remained largely unchanged between 1990 and 2015. To reduce this burden, effective population-level preventions strategies are required in addition to effective interventions of sufficient duration and coverage.


Assuntos
Efeitos Psicossociais da Doença , Carga Global da Doença , Transtornos Mentais/epidemiologia , Mortalidade Prematura , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Inquéritos Epidemiológicos , Humanos , Masculino , Transtornos Mentais/mortalidade , Pessoa de Meia-Idade , Prevalência , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
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