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1.
Elife ; 102021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33646943

RESUMO

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

2.
J Allied Health ; 50(1): 3-8, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646244

RESUMO

Rehabilitation, seen as a disability-specific service needed only by few of the world's population, has not been prioritized in countries and is under-resourced. A rehabilitation-ready health workforce is potentially the most important resource for improving functioning and the quality of life for the 2.41 billion people worldwide needing this care. In April 2019, CGFNS International, Inc., and the Association of Schools Advancing Health Professions (ASAHP) partnered to respond to the World Health Organization's Rehab 2030, which emphasizes the need for global action by professional organizations, development agencies, and civil society to develop and maintain a sustainable workforce for rehabilitation under different healthcare models in different economies. The global certification framework presented in this article provides a mechanism to validate rehabilitation knowledge and practice competence of individual health workers. The impact of certification on upgrading rehabilitation education and upskilling the world's rehabilitation health workforce cannot be overstated.

3.
Dev Psychopathol ; 32(4): 1303-1322, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33012299

RESUMO

Identifying developmental endophenotypes on the pathway between genetics and behavior is critical to uncovering the mechanisms underlying neurodevelopmental conditions. In this proof-of-principle study, we explored whether early disruptions in visual attention are a unique or shared candidate endophenotype of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We calculated the duration of the longest look (i.e., peak look) to faces in an array-based eye-tracking task for 335 14-month-old infants with and without first-degree relatives with ASD and/or ADHD. We leveraged parent-report and genotype data available for a proportion of these infants to evaluate the relation of looking behavior to familial (n = 285) and genetic liability (using polygenic scores, n = 185) as well as ASD and ADHD-relevant temperament traits at 2 years of age (shyness and inhibitory control, respectively, n = 272) and ASD and ADHD clinical traits at 6 years of age (n = 94).Results showed that longer peak looks at the face were associated with elevated polygenic scores for ADHD (ß = 0.078, p = .023), but not ASD (ß = 0.002, p = .944), and with elevated ADHD traits in mid-childhood (F(1,88) = 6.401, p = .013, $\eta _p^2$=0.068; ASD: F (1,88) = 3.218, p = .076), but not in toddlerhood (ps > 0.2). This pattern of results did not emerge when considering mean peak look duration across face and nonface stimuli. Thus, alterations in attention to faces during spontaneous visual exploration may be more consistent with a developmental endophenotype of ADHD than ASD. Our work shows that dissecting paths to neurodevelopmental conditions requires longitudinal data incorporating polygenic contribution, early neurocognitive function, and clinical phenotypic variation.

4.
Transl Psychiatry ; 10(1): 143, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398646

RESUMO

Epidemiological and biological evidence support the association between heavy cannabis use and psychosis. However, it is unclear which cannabis users are susceptible to its psychotogenic effect. Therefore, understanding genetic factors contributing to this relationship might prove an important strategy to identify the mechanisms underlying cannabis-associated psychotic experiences. We aimed to determine how variation in AKT1, COMT and FAAH genotypes, and their interaction with three different groups (first episode psychosis (FEP) patients (n = 143), controls (n = 92) and young adult (YA) cannabis users n = 485)) influenced cannabis experiences, in those who had used cannabis at least once. We investigated the role of AKT1 (rs2494732), COMT Val158Met (rs4680) and FAAH (rs324420) on cannabis experiences by combining data from a large case-control study of FEP patients, with a naturalistic study of YA cannabis users (n = 720). Outcome measures were cannabis-induced psychotic-like experiences (cPLEs) and euphoric experiences (cEEs). We used linear mixed effects models to assess the effects of each genotype and their interaction with group, adjusting for age, sex, ethnicity, age of first cannabis use, years of use and frequency. cPLEs were more frequent in FEP patients than controls and YA cannabis users. cEEs were more prevalent in YA cannabis users than FEP patients or controls. Variation in AKT1, COMT or FAAH was not associated with cPLEs/cEEs. There was no interaction between genotype and group (FEP cases, controls and YA cannabis users) on cPLEs/cEEs. In conclusion, AKT1, COMT or FAAH did not modulate specific psychotomimetic response to cannabis and did not interact with group, contrary to previous research.

5.
Behav Res Ther ; 123: 103503, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31715324

RESUMO

BACKGROUND: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research. METHODS: The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. RESULTS: Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants' questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages. DISCUSSION: This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression.


Assuntos
Ansiedade/genética , Depressão/genética , Seleção de Pacientes , Desenvolvimento de Programas/métodos , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Fenótipo , Transtornos Fóbicos/genética , Adulto Jovem
6.
PLoS One ; 14(10): e0223246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596875

RESUMO

BACKGROUND: Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants. METHODS: Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases. RESULTS: In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS. CONCLUSIONS: Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
7.
Genes Brain Behav ; 18(8): e12596, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31264367

RESUMO

The disrupted-in-schizophrenia 1 (DISC1) protein has been implicated in a range of biological mechanisms underlying chronic mental disorders such as schizophrenia. Schizophrenia is associated with abnormal striatal dopamine signalling, and all antipsychotic drugs block striatal dopamine 2/3 receptors (D2/3 Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D2 receptor (D2 R) that inhibits agonist-induced D2 R internalisation. Moreover, animal studies have found large striatal increases in the proportion of D2 R receptors in a high affinity state (D2 high R) in DISC1 rodent models. Here, we investigated the relationship between the three most common polymorphisms altering the amino-acid sequence of the DISC1 protein (Ser704Cys (rs821616), Leu607Phe (rs6675281) and Arg264Gln (rs3738401)) and striatal D2/3 R availability in 41 healthy human volunteers, using [11 C]-(+)-PHNO positron emission tomography. We found no association between DISC1 polymorphisms and D2/3 R availability in the striatum and D2 R availability in the caudate and putamen. Therefore, despite a direct interaction between DISC1 and the D2 R, none of its main functional polymorphisms impact striatal D2/3 R binding potential, suggesting DISC1 variants act through other mechanisms.


Assuntos
Corpo Estriado/diagnóstico por imagem , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Receptores Dopaminérgicos/metabolismo , Adulto , Corpo Estriado/metabolismo , Feminino , Humanos , Masculino , Oxazinas/farmacocinética , Tomografia por Emissão de Pósitrons , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética
8.
Brain Behav Immun ; 80: 644-656, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063847

RESUMO

Individuals with intact cognition and neuropathology consistent with Alzheimer's disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain "glutamate-glutamine cycle", and disturbances in the brain energy pathways in both AsymAD and AD subjects, while the connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Redes Reguladoras de Genes/genética , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Progressão da Doença , Feminino , Lobo Frontal/metabolismo , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Mitocôndrias/genética , Análise Serial de Tecidos/métodos , Transcriptoma/genética
9.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Criança , Humanos
10.
Schizophr Res ; 209: 88-97, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31113746

RESUMO

BACKGROUND: Psychosis is a condition influenced by an interaction of environmental and genetic factors. Gene expression studies can capture these interactions; however, studies are usually performed in patients who are in remission. This study uses blood of first episode psychosis patients, in order to characterise deregulated pathways associated with psychosis symptom dimensions. METHODS: Peripheral blood from 149 healthy controls and 131 first episode psychosis patients was profiled using Illumina HT-12 microarrays. A case/control differential expression analysis was performed, followed by correlation of gene expression with positive and negative syndrome scale (PANSS) scores. Enrichment analyses were performed on the associated gene lists. We test for pathway differences between first episode psychosis patients who qualify for a Schizophrenia diagnosis against those who do not. RESULTS: A total of 978 genes were differentially expressed and enriched for pathways associated to immune function and the mitochondria. Using PANSS scores we found that positive symptom severity was correlated with immune function, while negative symptoms correlated with mitochondrial pathways. CONCLUSIONS: Our results identified gene expression changes correlated with symptom severity and showed that key pathways are modulated by positive and negative symptom dimensions.


Assuntos
Transtornos Psicóticos/genética , Esquizofrenia/genética , Transcriptoma , Adolescente , Adulto , Transtornos Psicóticos Afetivos/genética , Transtornos Psicóticos Afetivos/psicologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Transtornos Psicóticos/psicologia , RNA/sangue , Psicologia do Esquizofrênico , Índice de Gravidade de Doença , Adulto Jovem
11.
Nat Commun ; 10(1): 1150, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850646

RESUMO

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.


Assuntos
Alopecia/congênito , Loci Gênicos , Predisposição Genética para Doença , Antígeno HLA-B7/genética , Transcriptoma/imunologia , Imunidade Adaptativa , Alopecia/diagnóstico , Alopecia/genética , Alopecia/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/imunologia , Feminino , Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Antígeno HLA-B7/imunologia , Humanos , Imunidade Inata , Polimorfismo de Nucleotídeo Único
12.
J Allergy Clin Immunol ; 143(6): 2120-2130, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578879

RESUMO

BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23). METHODS: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. RESULTS: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10-7), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10-5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.


Assuntos
Adalimumab/uso terapêutico , Terapia Biológica/métodos , Biomarcadores Farmacológicos , Genótipo , Antígenos HLA-C/genética , Psoríase/genética , Ustekinumab/uso terapêutico , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Prognóstico , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
13.
Nat Commun ; 9(1): 5075, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542056

RESUMO

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/patologia , Predisposição Genética para Doença/genética , Folículo Piloso/crescimento & desenvolvimento , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Laminina/biossíntese , Laminina/genética , Masculino , Proteínas de Membrana/metabolismo , Propionibacterium acnes/crescimento & desenvolvimento , Semaforinas/genética , Pele/patologia , Proteínas Wnt/genética
14.
Commun Biol ; 1: 163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30320231

RESUMO

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

15.
Transl Psychiatry ; 8(1): 174, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30171181

RESUMO

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS, we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered a p-value < 0.0014 (Bonferroni correction) as significant. First, we verified that the schizophrenia PRS was also able to distinguish cases from controls in this south-eastern Brazilian sample, with a similar variance explained to that seen in Northern European populations. In addition, within-cases analyses, we found that PRS is significantly correlated with baseline (pre-treatment) symptoms, as measured by lower clinical global assessment of functioning (-GAF), higher depressive symptoms and higher scores on a derived excitement factor. After standardized treatment for nine weeks, the correlation with GAF and the excitement factor disappeared while depressive symptoms became negatively associated with PRS. We conclude that drug (and other treatments) may confound attempts to understand the aetiological influence on symptomatology of polygenic risk scores. These results highlight the importance of studying schizophrenia, and other disorders, pre-treatment to understand the relationship between polygenic risk and phenotypic features.


Assuntos
Antipsicóticos/uso terapêutico , Predisposição Genética para Doença , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adolescente , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Medição de Risco , Risperidona/uso terapêutico , Adulto Jovem
16.
Eur Neuropsychopharmacol ; 28(8): 945-954, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30135031

RESUMO

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).


Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Variantes Farmacogenômicos , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Humanos
17.
Front Hum Neurosci ; 12: 7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29434543

RESUMO

Childhood maltreatment is associated with error hypersensitivity. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA) interaction on functional brain connectivity during error processing in medication/drug-free adolescents. Functional connectivity was compared, using generalized psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 22 age- and gender-matched medication-naïve and substance abuse-free adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed an individually adjusted tracking stop-signal task, designed to elicit 50% inhibition failures. During inhibition failures, abused participants relative to healthy controls exhibited reduced connectivity between right and left putamen, bilateral caudate and anterior cingulate cortex (ACC), and between right supplementary motor area (SMA) and right inferior and dorsolateral prefrontal cortex. Abuse-related connectivity abnormalities were associated with longer abuse duration. No group differences in connectivity were observed for successful inhibition. The findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-cingulo-striatal networks during error processing. Furthermore that the severity of connectivity abnormalities increases with abuse duration. Reduced connectivity of error detection networks in maltreated individuals may be linked to constant monitoring of errors in order to avoid mistakes which, in abusive contexts, are often associated with harsh punishment.

18.
PLoS One ; 12(11): e0188744, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29190830

RESUMO

Childhood maltreatment is associated with attention deficits. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA, FKBP5) interaction on functional brain connectivity during sustained attention in medication/drug-free adolescents. Functional connectivity was compared, using generalised psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 21 age-and gender-matched adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed a parametrically modulated vigilance task requiring target detection with a progressively increasing load of sustained attention. Behaviourally, participants exposed to childhood abuse had increased omission errors compared to healthy controls. During the most challenging attention condition abused participants relative to controls exhibited reduced connectivity, with a left-hemispheric bias, in typical fronto-parietal attention networks, including dorsolateral, rostromedial and inferior prefrontal and inferior parietal regions. Abuse-related connectivity abnormalities were exacerbated in individuals homozygous for the risky C-allele of the single nucleotide polymorphism rs3800373 of the FK506 Binding Protein 5 (FKBP5) gene. Findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-parietal attention networks and that the FKBP5 genotype moderates neurobiological vulnerability to abuse. These findings represent a first step towards the delineation of abuse-related neurofunctional connectivity abnormalities, which hopefully will facilitate the development of specific treatment strategies for victims of childhood maltreatment.


Assuntos
Mapeamento Encefálico , Maus-Tratos Infantis , Lobo Parietal/fisiopatologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Sci Rep ; 7(1): 14738, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116126

RESUMO

Many antipsychotics promote weight gain, which can lead to non-compliance and relapse of psychosis. By developing models that accurately identify individuals at greater risk of weight gain, clinicians can make informed treatment decisions and target intervention measures. We examined clinical, genetic and expression data for 284 individuals with psychosis derived from a previously published randomised controlled trial (IMPACT). These data were used to develop regression and classification models predicting change in Body Mass Index (BMI) over one year. Clinical predictors included demographics, anthropometrics, cardiac and blood measures, diet and exercise, physical and mental health, medication and BMI outcome measures. We included genetic polygenic risk scores (PRS) for schizophrenia, bipolar disorder, BMI, waist-hip-ratio, insulin resistance and height, as well as gene co-expression modules generated by Weighted Gene Co-expression Network Analysis (WGCNA). The best performing predictive models for BMI and BMI gain after one year used clinical data only, which suggests expression and genetic data do not improve prediction in this cohort.


Assuntos
Antipsicóticos/uso terapêutico , Índice de Massa Corporal , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Ganho de Peso/efeitos dos fármacos , Adulto , Antipsicóticos/efeitos adversos , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/genética , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Hum Mol Genet ; 26(21): 4301-4313, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973304

RESUMO

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.


Assuntos
Psoríase/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/fisiopatologia , Fatores de Risco , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequenciamento Completo do Exoma
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