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1.
Addict Biol ; 26(1): e12880, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064741

RESUMO

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

2.
Mar Drugs ; 18(11)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33227960

RESUMO

Tisochrysis lutea is a marine haptophyte rich in omega-3 polyunsaturated fatty acids (e.g., docosahexaenoic acid (DHA)) and carotenoids (e.g., fucoxanthin). Because of the nutraceutical applications of these compounds, this microalga is being used in aquaculture to feed oyster and shrimp larvae. In our earlier report, T. lutea organic crude extracts exhibited in vitro cytotoxic activity against human hepatocarcinoma (HepG2) cells. However, so far, the compound(s) accountable for the observed bioactivity have not been identified. Therefore, the aim of this study was to isolate and identify the chemical component(s) responsible for the bioactivity observed. Bioassay-guided fractionation through a combination of silica-gel column chromatography, followed by preparative thin layer chromatography (PTLC), led to the isolation of two diastereomers of a monoterpenoid lactone, namely, loliolide (1) and epi-loliolide (2), isolated for the first time in this species. The structural elucidation of both compounds was carried out by GC-MS and 1D (1H and 13C APT) and 2D (COSY, HMBC, HSQC-ed, and NOESY) NMR analysis. Both compounds significantly reduced the viability of HepG2 cells and were considerably less toxic towards a non-tumoral murine stromal (S17) cell line, although epi-loliolide was found to be more active than loliolide.

3.
Molecules ; 25(22)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238492

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and is characterized by a progressive degeneration of the dopaminergic neurons in the substantianigra. Although not completely understood, several abnormal cellular events are known to be related with PD progression, such as oxidative stress, mitochondrial dysfunction and apoptosis. Accordingly, the aim of this study was to evaluate the neuroprotective effects of Codium tomentosum enriched fractions in a neurotoxicity model mediated by 6-hydroxydopamine (6-OHDA) on SH-SY5Y human cells, and the disclosure of their mechanisms of action. Additionally, a preliminary chemical screening of the most promising bioactive fractions of C. tomentosum was carried out by GC-MS analysis. Among the tested fractions, four samples exhibited the capacity to revert the neurotoxicity induced by 6-OHDA to values higher or similar to the vitamin E (90.11 ± 3.74% of viable cells). The neuroprotective effects were mediated by the mitigation of reactive oxygen species (ROS) generation, mitochondrial dysfunctions and DNA damage, together with the reduction of Caspase-3 activity. Compounds belonging to different chemical classes, such as terpenes, alcohols, carboxylic acids, aldehydes, esters, ketones, saturated and unsaturated hydrocarbons were tentatively identified by GC-MS. The results show that C. tomentosum is a relevant source of neuroprotective agents, with particular interest for preventive therapeutics.

4.
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.

5.
Biomed Pharmacother ; 128: 110275, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32480221

RESUMO

Cancer is one of the major threats to human health and, due to distinct factors, it is expected that its incidence will increase in the next decades leading to an urgent need of new anticancer drugs development. Ongoing experimental and clinical observations propose that cancer cells with stem-like properties (CSCs) are involved on the development of lung cancer chemoresistance. As tumour growth and metastasis can be controlled by tumour-associated stromal cells, the main goal of this study was to access the antitumor potential of five bromoterpenes isolated from Sphaerococcus coronopifolius red alga to target CSCs originated in a co-culture system of fibroblast and lung malignant cells. Cytotoxicity of compounds (10-500 µM; 72 h) was evaluated on monocultures of several malignant and non-malignant cells lines (HBF, BEAS-2B, RenG2, SC-DRenG2) and the effects estimated by MTT assay. Co-cultures of non-malignant human bronchial fibroblasts (HBF) and malignant human bronchial epithelial cells (RenG2) were implemented and the compounds ability to selectively kill CSCs was evaluated by sphere forming assay. The interleucine-6 (IL-6) levels were also determined as cytokine is crucial for CSCs. Regarding the monocultures results bromosphaerol selectively eliminated the malignant cells. Both 12S-hydroxy-bromosphaerol and 12R-hydroxy-bromosphaerol steroisomers were cytotoxic towards non-malignant bronchial BEAS-2B cell line, IC50 of 4.29 and 4.30 µM respectively. However, none of the steroisomers induced damage in the HBFs. As to the co-cultures, 12R-hydroxy-bromosphaerol revealed the highest cytotoxicity and ability to abrogate the malignant stem cells; however its effects were IL-6 independent. The results presented here are the first evidence of the potential of these bromoterpenes to abrogate CSCs opening new research opportunities. The 12R-hydroxy-bromosphaerol revealed to be the most promising compound to be test in more complex living models.

6.
J Anal Toxicol ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32588896

RESUMO

The emergence of potentially dangerous new psychoactive substances (NPS) is challenging for forensic laboratories, as well as the ability to develop and validate methods for a rapid and unambiguous monitoring of these compounds. Thereupon, the aim of this work was to establish a methodology for the identification and quantification of four synthetic cathinones already seized in Portugal [4-chloroethcathinone (4-CEC), α-pyrrolidinovalerophenone (α-PVP), 4-chloro-pyrrolidinovalerophenone (4-Cl-PVP) and methylenedioxypyrovalerone (MDPV)] in whole blood samples, using gas chromatography coupled to mass spectrometry (GC-MS). The analytes were extracted from blood by solid-phase extraction (SPE) and derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) with 5% trimethylchlorosilane (TMCS). For all analytes, linearity was observed from 25 (lower limit of quantification, LLOQ) to 800 ng/mL, with coefficients of determination higher than 0.99. The limits of detection (LOD) were 5 ng/mL for α-PVP, 4-Cl-PVP and MDPV and 25 ng/mL for 4-CEC. The method was selective, precise and accurate and the extraction efficiency was higher than 85% for all analytes. The target cathinones were stable under different stock conditions, being MDPV the most stable and 4-CEC the least stable compound. The validated analytical method was then applied to real samples that previously tested positive for amphetamines, but no positive samples were found for the cathinones under study. The present method describes for the first time the quantification of 4-CEC and 4-Cl-PVP in whole blood samples by GC-MS, allowing their accurate determination in forensic situations where the compounds are involved.

8.
Arch Toxicol ; 94(7): 2481-2503, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382956

RESUMO

Cathinones (ß-keto amphetamines), widely abused in recreational settings, have been shown similar or even worse toxicological profile than classical amphetamines. In the present study, the cytotoxicity of two ß-keto amphetamines [3,4-dimethylmethcathinone (3,4-DMMC) and 4-methylmethcathinone (4-MMC)], was evaluated in differentiated dopaminergic SH-SY5Y cells in comparison to methamphetamine (METH). MTT reduction and NR uptake assays revealed that both cathinones and METH induced cytotoxicity in a concentration- and time-dependent manner. Pre-treatment with trolox (antioxidant) partially prevented the cytotoxicity induced by all tested drugs, while N-acetyl-L-cysteine (NAC; antioxidant and glutathione precursor) and GBR 12909 (dopamine transporter inhibitor) partially prevented the cytotoxicity induced by cathinones, as evaluated by the MTT reduction assay. Unlike METH, cathinones induced oxidative stress evidenced by the increase on intracellular levels of reactive oxygen species (ROS), and also by the decrease of intracellular glutathione levels. Trolox prevented, partially but significantly, the ROS generation elicited by cathinones, while NAC inhibited it completely. All tested drugs induced mitochondrial dysfunction, since they led to mitochondrial membrane depolarization and to intracellular ATP depletion. Activation of caspase-3, indicative of apoptosis, was seen both for cathinones and METH, and confirmed by annexin V and propidium iodide positive staining. Autophagy was also activated by all drugs tested. Pre-incubation with bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, only protected against the cytotoxicity induced by METH, which indicates dissimilar toxicological pathways for the tested drugs. In conclusion, the mitochondrial impairment and oxidative stress observed for the tested cathinones may be key factors for their neurotoxicity, but different outcome pathways seem to be involved in the adverse effects, when compared to METH.

9.
Biol Psychiatry ; 88(2): 169-184, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926635

RESUMO

BACKGROUND: Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. METHODS: To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). RESULTS: Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment-the relationship is positive in bipolar disorder but negative in major depressive disorder. CONCLUSIONS: The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

10.
Mol Psychiatry ; 25(7): 1430-1446, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31969693

RESUMO

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

11.
Toxicol Lett ; 319: 129-137, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730886

RESUMO

The increasing use of synthetic cannabinoids (SCBs) in recreational settings is becoming a new paradigm of drug abuse. Although SCBs effects mimic those of the Cannabis sativa plant, these drugs are frequently more potent and hazardous. It is known that endocannabinoid signalling plays a crucial role in diverse reproductive events such as placental development. Moreover, the negative impact of the phytocannabinoid Δ9-tetrahydrocannabinol (THC) in pregnancy outcome, leading to prematurity, intrauterine growth restriction and low birth weight is well recognized, which makes women of childbearing age a sensitive group to developmental adverse effects of cannabinoids. Placental trophoblast turnover relies on regulated processes of proliferation and apoptosis for normal placental development. Here, we explored the impact of the SCBs JWH-018, JWH-122 and UR-144 and of the phytocannabinoid THC in BeWo cell line, a human placental cytotrophoblast cell model. All the cannabinoids caused a significant decrease in cell viability without LDH release, though this effect was only detected for the highest concentrations of THC. Moreover, a cell cycle arrest at the G2/M phase was also observed. JWH-018 and JWH-122 increased reactive oxygen species (ROS) production and THC, UR-144 and JWH-122 caused loss of mitochondrial membrane potential. All the compounds were able to induce caspase-9 activation. The involvement of apoptotic pathways was further confirmed through the significant increase in caspase -3/-7 activities. For UR-144, this effect was reversed by the CB1 antagonist AM281, for JWH-018 and THC this effect was mediated by both cannabinoid receptors CB1 and CB2 while for JWH-122 it was cannabinoid receptor-independent. This work demonstrates that THC and SCBs are able to induce apoptotic cell death. Although they may act through different mechanisms and potencies, the studied cannabinoids have the potential to disrupt gestational fundamental events.


Assuntos
Apoptose/efeitos dos fármacos , Canabinoides/toxicidade , Dronabinol/toxicidade , Indóis/toxicidade , Naftalenos/toxicidade , Placenta/citologia , Placenta/efeitos dos fármacos , Adulto , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Trofoblastos/efeitos dos fármacos
12.
Mol Psychiatry ; 25(12): 3292-3303, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748690

RESUMO

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

13.
Nat Commun ; 10(1): 5765, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852892

RESUMO

Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.


Assuntos
Glicemia/genética , Composição Corporal/genética , Transtornos Mentais/genética , Sobrepeso/genética , Fatores Etários , Comorbidade , Escolaridade , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/prevenção & controle , Pessoa de Meia-Idade , Herança Multifatorial/genética , Sobrepeso/epidemiologia , Fenótipo , Aptidão Física , Fatores de Risco , Fatores Sexuais
14.
Nat Genet ; 51(12): 1670-1678, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31740837

RESUMO

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Estudos de Casos e Controles , Extremo Oriente , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos
15.
Neurotoxicology ; 75: 158-173, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31473217

RESUMO

Synthetic cathinones also known as ß-keto amphetamines are a new group of recreational designer drugs. We aimed to evaluate the cytotoxic potential of thirteen cathinones lacking the methylenedioxy ring and establish a putative structure-toxicity profile using differentiated SH-SY5Y cells, as well as to compare their toxicity to that of amphetamine (AMPH) and methamphetamine (METH). Cytotoxicity assays [mitochondrial 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction and lysosomal neutral red (NR) uptake] performed after a 24-h or a 48-h exposure revealed for all tested drugs a concentration-dependent toxicity. The rank order regarding the concentration that promoted 50 % of toxicity, at 24 h exposure, by the MTT assay was: 3,4-dimethylmethcathinone (3,4-DMMC) > METH > mephedrone ≈ α-pyrrolidinopentiophenone > AMPH ≈ methedrone > pentedrone > buphedrone ≈ flephedrone >α-pyrrolidinobutiophenone > methcathinone ≈ N-ethylcathinone >α-pyrrolidinopropiophenone >N,N-dimethylcathinone ≈ amfepramone. Apoptotic cell death signs were seen for all studied cathinones. 3,4-DMMC, methcathinone and pentedrone triggered autophagy activation, as well as increased reactive oxygen species production, and N-acetyl-L-cysteine (NAC) totally prevented that rise. Importantly, NAC was also able to prevent the cytotoxicity promoted by 6 tested drugs, ruling for an involvement of oxidative stress in the toxic events observed. The increased lipophilic chain on the alpha carbon, the presence and the high steric volume occupied by the substituents on the aromatic ring, and the substitution of the pyrrolidine ring by its secondary amine analogue have proved to be key points for the cytotoxicity profile of these cathinones. The structure-toxicity relationship established herein may enlighten future human relevant mechanistic studies, and future clinical approaches on intoxications.


Assuntos
Alcaloides/toxicidade , Anfetaminas/toxicidade , Neurônios/efeitos dos fármacos , Alcaloides/química , Anfetaminas/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Microscopia de Contraste de Fase , Neurônios/ultraestrutura , Propiofenonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
16.
Behav Res Ther ; 121: 103413, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31491689

RESUMO

The majority of those who experience clinical anxiety and/or depressive symptoms in the population do not receive treatment. Studies investigating inequalities in treatment outcomes rarely consider that individuals respond differently to their experience of the environment. Much of our environment is under genetic influence, via our behaviour, whereby individuals actively select their experiences. If genes influence who seeks and receives treatment, selection bias will confound genomic studies of treatment response. Furthermore, if some individuals are at high genetic risk of needing but not commencing treatment, then greater efforts could be made to engage them. The role of common genetic variation on four lifetime treatment-seeking behaviours (treatment-seeking, treatment-receipt, self-help, self-medication with alcohol/drugs) was examined in participants of the UK Biobank (sample size range: 48,106 - 75,322). Treatment-related behaviours were only modestly heritable in these data. Nonetheless, genetic correlations reveal substantial genetic overlap between lifetime treatment-related behaviours and psychiatric disorders, symptoms and behavioural traits. To our knowledge, this is the first study to examine genetic influences on treatment-related behaviours. Further work is required to determine whether genetic factors could be used alongside clinical, social and demographic factors to identify at risk groups and inform strategies which target early intervention.


Assuntos
Ansiedade/genética , Depressão/genética , Transtornos Mentais/genética , Adulto , Ansiedade/terapia , Bancos de Espécimes Biológicos , Depressão/terapia , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Transtornos Mentais/terapia , Saúde Mental , Aceitação pelo Paciente de Cuidados de Saúde , Fenótipo , Fatores de Risco , Autogestão , Reino Unido
17.
Int J Methods Psychiatr Res ; 28(3): e1796, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397039

RESUMO

OBJECTIVES: For many research cohorts, it is not practical to provide a "gold-standard" mental health diagnosis. It is therefore important for mental health research that potential alternative measures for ascertaining mental disorder status are understood. METHODS: Data from UK Biobank in those participants who had completed the online Mental Health Questionnaire (n = 157,363) were used to compare the classification of mental disorder by four methods: symptom-based outcome (self-complete based on diagnostic interviews), self-reported diagnosis, hospital data linkage, and self-report medication. RESULTS: Participants self-reporting any psychiatric diagnosis had elevated risk of any symptom-based outcome. Cohen's κ between self-reported diagnosis and symptom-based outcome was 0.46 for depression, 0.28 for bipolar affective disorder, and 0.24 for anxiety. There were small numbers of participants uniquely identified by hospital data linkage and medication. CONCLUSION: Our results confirm that ascertainment of mental disorder diagnosis in large cohorts such as UK Biobank is complex. There may not be one method of classification that is right for all circumstances, but an informed and transparent use of outcome measure(s) to suit each research question will maximise the potential of UK Biobank and other resources for mental health research.


Assuntos
Transtornos Mentais/classificação , Transtornos Mentais/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Autorrelato , Adulto , Estudos de Coortes , Bases de Dados Factuais , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Sistemas Computadorizados de Registros Médicos , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Reino Unido/epidemiologia
18.
Nat Genet ; 51(8): 1207-1214, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308545

RESUMO

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.


Assuntos
Anorexia Nervosa/etiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Transtornos Mentais/complicações , Doenças Metabólicas/complicações , Locos de Características Quantitativas , Adulto , Anorexia Nervosa/genética , Anorexia Nervosa/patologia , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Transtornos Mentais/genética , Doenças Metabólicas/genética , Fenótipo , Prognóstico
19.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
20.
BMC Bioinformatics ; 20(1): 116, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845922

RESUMO

BACKGROUND: Principal component analysis (PCA) is a standard method to correct for population stratification in ancestry-specific genome-wide association studies (GWASs) and is used to cluster individuals by ancestry. Using the 1000 genomes project data, we examine how non-linear dimensionality reduction methods such as t-distributed stochastic neighbor embedding (t-SNE) or generative topographic mapping (GTM) can be used to provide improved ancestry maps by accounting for a higher percentage of explained variance in ancestry, and how they can help to estimate the number of principal components necessary to account for population stratification. GTM generates posterior probabilities of class membership which can be used to assess the probability of an individual to belong to a given population - as opposed to t-SNE, GTM can be used for both clustering and classification. RESULTS: PCA only partially identifies population clusters and does not separate most populations within a given continent, such as Japanese and Han Chinese in East Asia, or Mende and Yoruba in Africa. t-SNE and GTM, taking into account more data variance, can identify more fine-grained population clusters. GTM can be used to build probabilistic classification models, and is as efficient as support vector machine (SVM) for classifying 1000 Genomes Project populations. CONCLUSION: The main interest of probabilistic GTM maps is to attain two objectives with only one map: provide a better visualization that separates populations efficiently, and infer genetic ancestry for individuals or populations. This paper is a first application of GTM for ancestry classification models. Our code ( https://github.com/hagax8/ancestry_viz ) and interactive visualizations ( https://lovingscience.com/ancestries ) are available online.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Genética Populacional , Modelos Estatísticos , Arabidopsis/genética , Análise por Conglomerados , Estudo de Associação Genômica Ampla , Humanos , Análise de Componente Principal , Processos Estocásticos
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