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1.
Mol Psychiatry ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014000

RESUMO

Genome-Wide Association Studies (GWAS) over-represent European ancestries, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to Africans. We assessed the comparative accuracy of depression PRS trained on European and African Ancestries GWAS studies to predict major depressive disorder (MDD) and related traits in African ancestry participants from the UK Biobank. UK Biobank participants were selected based on Principal component analysis clustering with an African genetic similarity reference population, MDD was assessed with the Composite International Diagnostic Interview (CIDI). PRS were computed using PRSice2 software using either European or African Ancestries GWAS summary statistics. PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (R2 = 2%, ß = 0.32, empirical p-value = 0.002) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R² = 1.8%, ß = 0.28, empirical p-value = 0.008). This suggests that prediction of MDD status from Africans to Africans had greater efficiency relative to discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of likely causal risk factors from European ancestries was non-significant. GWAS of MDD in European ancestries are inefficient for improving polygenic prediction in African samples; urgent MDD studies in Africa are needed.

2.
Phys Rev Lett ; 131(24): 241802, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38181129

RESUMO

We demonstrate the feasibility of probing the charged lepton-flavor-violating decay µ^{+}→e^{+}X^{0} for the presence of a slow-moving neutral boson X^{0} capable of undergoing gravitational binding to large structures and, as such, able to participate in some cosmological scenarios. A short exposure to surface antimuons from beam line M20 at TRIUMF generates a branching ratio limit of ≲10^{-5}. This is comparable to or better than previous searches for this channel, although in a thus-far-unexplored region of X^{0} phase space very close to the kinematic limit of the decay, where m_{X^{0}} approaches m_{µ^{+}}. The future improved sensitivity of the method using a customized p-type point-contact germanium detector is described.

3.
Phys Rev Lett ; 129(21): 211802, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36461969

RESUMO

The 96.4 day exposure of a 3 kg ultralow noise germanium detector to the high flux of antineutrinos from a power nuclear reactor is described. A very strong preference (p<1.2×10^{-3}) for the presence of a coherent elastic neutrino-nucleus scattering (CEνNS) component in the data is found, when compared to a background-only model. No such effect is visible in 25 days of operation during reactor outages. The best-fit CEνNS signal is in good agreement with expectations based on a recent characterization of germanium response to sub-keV nuclear recoils. Deviations of order 60% from the standard model CEνNS prediction can be excluded using present data. Standing uncertainties in models of germanium quenching factor, neutrino energy spectrum, and background are examined.

4.
Pharmacogenomics J ; 18(3): 413-421, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29160301

RESUMO

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Estudo de Associação Genômica Ampla , Farmacogenética/tendências , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Variação Genética , Genótipo , Humanos , Integrinas/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento
5.
Brain Behav Immun ; 67: 203-210, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28867280

RESUMO

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/imunologia , Inflamação/genética , Inflamação/imunologia , Adulto , Sobreviventes Adultos de Maus-Tratos Infantis , Proteína C-Reativa/genética , Estudos de Casos e Controles , Transtorno Depressivo Maior/complicações , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
6.
Pharmacogenomics J ; 17(5): 395-402, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28607506

RESUMO

Pharmacogenetics (PGx) has the potential to personalize pharmaceutical treatments. Many relevant gene-drug associations have been discovered, but PGx-guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard health-care. We reviewed economic evaluations for PGx associations listed in the US Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling. We determined the proportion of evaluations that found PGx-guided treatment to be cost-effective or dominant over the alternative strategies, and estimated the impact on this proportion of removing the cost of genetic testing. Of the 137 PGx associations in the FDA table, 44 economic evaluations, relating to 10 drugs, were identified. Of these evaluations, 57% drew conclusions in favour of PGx testing, of which 30% were cost-effective and 27% were dominant (cost-saving). If genetic information was freely available, 75% of economic evaluations would support PGx-guided treatment, of which 25% would be cost-effective and 50% would be dominant. Thus, PGx-guided treatment can be a cost-effective and even a cost-saving strategy. Having genetic information readily available in the clinical health record is a realistic future prospect, and would make more genetic tests economically worthwhile.


Assuntos
Farmacoeconomia , Farmacogenética/economia , Testes Farmacogenômicos/economia , Medicina de Precisão/economia , Análise Custo-Benefício , Estados Unidos , United States Food and Drug Administration
7.
Psychol Med ; 46(4): 759-70, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26526099

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Transtorno Depressivo Maior/genética , Interação Gene-Ambiente , Acontecimentos que Mudam a Vida , Herança Multifatorial , Estresse Psicológico/genética , Adulto , Adultos Sobreviventes de Eventos Adversos na Infância/estatística & dados numéricos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , Adulto Jovem
8.
Pharmacogenomics J ; 15(5): 461-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25732907

RESUMO

Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high-risk and a low-risk group, we explore the relationship between test sensitivity, group size and agranulocytosis risk. High sensitivity minimizes the agranulocytosis risk in the low-risk group and is essential for clinical utility, in particular in combination with a small high-risk group.


Assuntos
Agranulocitose/genética , Clozapina/efeitos adversos , Cadeias beta de HLA-DQ/genética , Esquizofrenia/tratamento farmacológico , Agranulocitose/induzido quimicamente , Clozapina/administração & dosagem , Hipersensibilidade a Drogas/genética , Feminino , Humanos , Farmacogenética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/genética
9.
Psychol Med ; 45(9): 1945-54, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25781917

RESUMO

BACKGROUND: Do DSM-IV diagnostic criteria for major depression (MD) in Chinese and Western women perform in a similar manner? METHOD: The CONVERGE study included interview-based assessments of women of Han Chinese descent with treated recurrent MD. Using Mplus software, we investigated the overall degree of between-sample measurement invariance (MI) for DSM-IV diagnostic criteria for MD in the CONVERGE sample and samples selected from four major Western studies from the USA and Europe matched to the inclusion criteria of CONVERGE. These analyses were performed one pair at a time. We then compared the results from CONVERGE paired with Western samples to those obtained when examining levels of MI between pairs of the Western samples. RESULTS: Assuming a single factor model for the nine diagnostic criteria for MD, the level of MI based on global fit indexes observed between the CONVERGE and the four Western samples was very similar to that seen between the Western samples. Comparable results were obtained when using a two-factor structure for MI testing when applied to the 14 diagnostic criteria for MD disaggregated for weight, appetite, sleep, and psychomotor changes. CONCLUSIONS: Despite differences in language, ethnicity and culture, DSM criteria for MD perform similarly in Chinese women with recurrent MD and comparable subjects from the USA and Europe. The DSM criteria for MD may assess depressive symptoms that are relatively insensitive to cultural and ethnic differences. These results support efforts to compare findings from depressed patients in China and Western countries.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Adulto , China , Assistência à Saúde Culturalmente Competente , Transtorno Depressivo Maior/etnologia , Transtorno Depressivo Maior/psicologia , Europa (Continente) , Feminino , Humanos , Pessoa de Meia-Idade , Estados Unidos
10.
Psychol Med ; 45(10): 2215-25, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25698070

RESUMO

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Alemanha , Humanos , Entrevistas como Assunto , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Irmãos , Reino Unido , Adulto Jovem
11.
Mol Psychiatry ; 19(10): 1085-94, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24514567

RESUMO

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.


Assuntos
Anorexia Nervosa/genética , Povo Asiático/genética , Calcineurina/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Proteínas Culina/genética , Feminino , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Japão , Masculino , Metanálise como Assunto , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética
12.
Mol Psychiatry ; 19(4): 452-61, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23568192

RESUMO

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.


Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Hipocampo/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fenótipo , RNA Mensageiro/metabolismo , População Branca/genética
13.
Pharmacogenomics J ; 14(5): 411-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24732178

RESUMO

Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutamatos/efeitos adversos , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Progressão da Doença , Glutamatos/farmacologia , Guanina/efeitos adversos , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Pemetrexede , Estudos Retrospectivos , Taxa de Sobrevida
14.
Mol Psychiatry ; 18(2): 183-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22042228

RESUMO

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.


Assuntos
Variações do Número de Cópias de DNA/genética , Transtorno Depressivo/genética , Predisposição Genética para Doença , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Recidiva
15.
Br J Cancer ; 108(12): 2505-15, 2013 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-23736036

RESUMO

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Citidina Desaminase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neoplasias/diagnóstico , Timidilato Sintase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Citidina Desaminase/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Fluoruracila/uso terapêutico , Variação Genética/fisiologia , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Modelos Genéticos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/genética , Farmacogenética , Prognóstico , Fatores de Risco , Timidilato Sintase/fisiologia , Adulto Jovem
16.
Br J Cancer ; 108(4): 762-5, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23322195

RESUMO

BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Indóis/administração & dosagem , Pirazinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Bortezomib , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Sunitinibe , Neoplasias da Glândula Tireoide/tratamento farmacológico
17.
Psychol Med ; 43(9): 1965-71, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23237013

RESUMO

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.


Assuntos
Acontecimentos que Mudam a Vida , Personalidade/genética , Irmãos/psicologia , Transtornos de Ansiedade , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Neuroticismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Meio Social
18.
Theor Appl Genet ; 126(6): 1599-612, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23536048

RESUMO

Stripe rust resistance in the winter wheat cultivar Claire had remained effective in the UK and Europe since its release in 1999 and consequently has been used extensively in wheat breeding programs. However, in 2012, reports indicated that this valuable resistance may now have been compromised. To characterise stripe rust resistance in Claire and determine which genes may still confer effective resistance a cross was made between Claire and the stripe rust susceptible cultivar Lemhi. A genetic linkage map, constructed using SSR, AFLP, DArT and NBS-AFLP markers had a total map length of 1,730 cM. To improve the definition of two quantitative trait loci (QTL) identified on the long arm of chromosome 2D further markers were developed from wheat EST. Stripe rust resistance was evaluated on adult plants under field and glasshouse conditions by measuring the extent of fungal growth and sporulation, percentage infection (Pi) and the necrotic/chlorotic responses of the plant to infection, infection type (IT). Four QTL contributing to stripe rust adult plant resistance (APR) were identified in Claire, QYr.niab-2D.1, QYr.niab-2D.2, QYr.niab-2B and QYr.niab-7B. For Pi QYr.niab-2D.1 explained up to 25.4 % of the phenotypic variation, QYr.niab-2D.2 up to 28.7 %, QYr.niab-2B up to 21.7 % and QYr.niab-7B up to 13.0 %. For IT the percentages of phenotypic variation explained were 23.4, 31.8, 17.2 and 12.6 %, respectively. In addition to the four QTL conferring APR in Claire, a race-specific, seedling expressed resistance gene was identified on chromosome 3B.


Assuntos
Basidiomycota , Resistência à Doença/genética , Genes de Plantas/genética , Doenças das Plantas/microbiologia , Locos de Características Quantitativas/genética , Triticum/genética , Agricultura/métodos , Mapeamento Cromossômico , Marcadores Genéticos/genética , Reino Unido
19.
Mol Psychiatry ; 17(9): 867-74, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22688189

RESUMO

Twin studies allow us to estimate the relative contributions of nature and nurture to human phenotypes by comparing the resemblance of identical and fraternal twins. Variation in complex traits is a balance of genetic and environmental influences; these influences are typically estimated at a population level. However, what if the balance of nature and nurture varies depending on where we grow up? Here we use statistical and visual analysis of geocoded data from over 6700 families to show that genetic and environmental contributions to 45 childhood cognitive and behavioral phenotypes vary geographically in the United Kingdom. This has implications for detecting environmental exposures that may interact with the genetic influences on complex traits, and for the statistical power of samples recruited for genetic association studies. More broadly, our experience demonstrates the potential for collaborative exploratory visualization to act as a lingua franca for large-scale interdisciplinary research.


Assuntos
Doenças em Gêmeos/epidemiologia , Interação Gene-Ambiente , Mapeamento Geográfico , Modelos Estatísticos , Estudos em Gêmeos como Assunto/estatística & dados numéricos , Criança , Doenças em Gêmeos/genética , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Reino Unido/epidemiologia
20.
Mol Psychiatry ; 17(6): 604-11, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21502950

RESUMO

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.


Assuntos
Índice de Massa Corporal , Transtorno Depressivo Maior/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Proteínas/genética , Proteínas/fisiologia , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estudos de Casos e Controles , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/fisiopatologia , Feminino , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/psicologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia
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