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1.
Am J Hum Genet ; 111(1): 133-149, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38181730

RESUMO

Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.


Assuntos
Regulação da Expressão Gênica , Locos de Características Quantitativas , Humanos , Locos de Características Quantitativas/genética , Genótipo , Fenótipo
2.
Psychol Med ; 54(5): 874-885, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37882058

RESUMO

BACKGROUND: Trauma is prevalent amongst early psychosis patients and associated with adverse outcomes. Past trials of trauma-focused therapy have focused on chronic patients with psychosis/schizophrenia and comorbid Post-Traumatic Stress Disorder (PTSD). We aimed to determine the feasibility of a large-scale randomized controlled trial (RCT) of an Eye Movement Desensitization and Reprocessing for psychosis (EMDRp) intervention for early psychosis service users. METHODS: A single-blind RCT comparing 16 sessions of EMDRp + TAU v. TAU only was conducted. Participants completed baseline, 6-month and 12-month post-randomization assessments. EMDRp and trial assessments were delivered both in-person and remotely due to COVID-19 restrictions. Feasibility outcomes were recruitment and retention, therapy attendance/engagement, adherence to EMDRp treatment protocol, and the 'promise of efficacy' of EMDRp on relevant clinical outcomes. RESULTS: Sixty participants (100% of the recruitment target) received TAU or EMDR + TAU. 83% completed at least one follow-up assessment, with 74% at 6-month and 70% at 12-month. 74% of EMDRp + TAU participants received at least eight therapy sessions and 97% rated therapy sessions demonstrated good treatment fidelity. At 6-month, there were signals of promise of efficacy of EMDRp + TAU v. TAU for total psychotic symptoms (PANSS), subjective recovery from psychosis, PTSD symptoms, depression, anxiety, and general health status. Signals of efficacy at 12-month were less pronounced but remained robust for PTSD symptoms and general health status. CONCLUSIONS: The trial feasibility criteria were fully met, and EMDRp was associated with promising signals of efficacy on a range of valuable clinical outcomes. A larger-scale, multi-center trial of EMDRp is feasible and warranted.


Assuntos
Dessensibilização e Reprocessamento através dos Movimentos Oculares , Transtornos Psicóticos , Esquizofrenia , Transtornos de Estresse Pós-Traumáticos , Humanos , Dessensibilização e Reprocessamento através dos Movimentos Oculares/métodos , Estudos de Viabilidade , Transtornos Psicóticos/terapia , Esquizofrenia/terapia , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Resultado do Tratamento
3.
Circ Res ; 131(2): e51-e69, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35658476

RESUMO

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.


Assuntos
Arsênio , Aterosclerose , Doenças Cardiovasculares , Animais , Apolipoproteínas E , Arsênio/toxicidade , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Metilação de DNA , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos
4.
Hum Mol Genet ; 31(2): 309-319, 2021 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-34415308

RESUMO

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P < 1 × 10-7), with a 0.7-3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes [PR/SET domain 16, nuclear receptor subfamily 1 group H member 3 (NR1H3), DNA repair protein, DNA polymerase kappa and decaprenyl-diphosphate synthase subunit 2], which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, P = 4 × 10-8) and was positively associated with the NR1H3 expression level (effect size = 0.43, P = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.


Assuntos
Epigenoma , Genoma Mitocondrial , Idoso , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Epigenoma/genética , Feminino , Genoma Mitocondrial/genética , Humanos , Masculino , Pessoa de Meia-Idade
5.
Psychol Med ; 53(7): 2954-2962, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-34991770

RESUMO

BACKGROUND: Post-traumatic mechanisms are theorised to contribute to voice-hearing in people with psychosis and a history of trauma. Phenomenological links between trauma and voices support this hypothesis, as they suggest post-traumatic processes contribute to the content of, and relationships with, voices. However, research has included small samples and lacked theory-based comprehensive assessments. METHOD: In people with distressing voices (n = 73) who experienced trauma prior to voice-hearing, trauma-voice links were assessed both independently and dependently (descriptions were presented and rated separately and together, respectively) by both participants and researchers. A structured coding frame assessed four types of independent links (i.e. victimisation type, physiological-behavioural, emotional, and cognitive response themes including negative self-beliefs) and three types of dependent links: relational (similar interaction with/response to, voice and trauma); content (voice and trauma content are exactly the same); and identity (voice identity is the same as perpetrator). RESULTS: Independent links were prevalent in participants (51-58%) and low to moderately present in researcher ratings (8-41%) for significant themes. Identification of negative self-beliefs in trauma was associated with a significantly higher likelihood of negative self-beliefs in voices [participants odds ratio (OR) 9.8; researchers OR 4.9]. Participants and researchers also reported many dependent links (80%, 66%, respectively), most frequently relational links (75%, 64%), followed by content (60%, 25%) and identity links (51%, 22%). CONCLUSION: Trauma appears to be a strong shaping force for voice content and its psychological impact. The most common trauma-voice links involved the experience of cognitive-affective psychological threat, embodied in relational experiences. Trauma-induced mechanisms may be important intervention targets.


Assuntos
Transtornos Psicóticos , Voz , Humanos , Alucinações/etiologia , Alucinações/psicologia , Transtornos Psicóticos/psicologia , Emoções
6.
Am J Respir Crit Care Med ; 206(3): 321-336, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35536696

RESUMO

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.


Assuntos
Metilação de DNA , Epigenoma , Ilhas de CpG , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Pulmão
7.
J Trauma Stress ; 36(2): 299-309, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36719408

RESUMO

Concern for symptom exacerbation and treatment drop-out is an important barrier to the implementation of trauma-focused therapy (TFT), especially in people with a psychotic disorder. This study, which was part of a multicenter randomized controlled trial, investigated posttraumatic stress disorder (PTSD) symptom exacerbation during eye movement desensitization reprocessing (EMDR) therapy and prolonged exposure (PE) in a sample of 99 participants with PTSD and psychosis. Symptom exacerbations during the first four sessions (early exacerbation) and between-session exacerbations over the course of therapy were monitored using the PTSD Symptom Scale-Self Report. Analyses of covariance and chi-square tests were conducted to investigate exacerbation rates and their associations with treatment response and drop-out. Both early exacerbation and between-session exacerbation were relatively common (32.3% and 46.5%, respectively) but were unrelated to poor treatment response or an increased likelihood of treatment drop-out. Both clinicians and patients need to be aware that symptom exacerbation during TFT is common and not related to poor outcomes. Symptom exacerbation can be part of the therapeutic process, should be acknowledged and guided, and should not be a barrier to the implementation of TFT in people with psychosis.


Assuntos
Dessensibilização e Reprocessamento através dos Movimentos Oculares , Transtornos Psicóticos , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/terapia , Exacerbação dos Sintomas , Psicoterapia
8.
Psychol Med ; 51(14): 2485-2492, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32419682

RESUMO

BACKGROUND: Understanding the interplay between trauma-related psychological mechanisms and psychotic symptoms may improve the effectiveness of interventions for post-traumatic stress reactions in psychosis. Network theory assumes that mental health problems persist not because of a common latent variable, but from dynamic feedback loops between symptoms, thereby addressing the heterogeneous and overlapping nature of traumagenic and psychotic diagnoses. This is a proof-of-concept study examining interactions between post-traumatic stress symptoms, which were hypothesized to reflect trauma-related psychological mechanisms, and auditory hallucinations and delusions. METHOD: Baseline data from two randomised controlled trials (N = 216) of trauma-focused therapy in people with post-traumatic stress symptoms (87.5% met diagnostic criteria for PTSD) and psychotic disorder were analysed. Reexperiencing, hyperarousal, avoidance, trauma-related beliefs, auditory hallucinations and delusional beliefs were used to estimate a Gaussian graphical model along with expected node influence and predictability (proportion of explained variance). RESULTS: Trauma-related beliefs had the largest direct influence on the network and, together with hypervigilance, were implicated in the shortest paths from flashbacks to delusions and auditory hallucinations. CONCLUSIONS: These findings are in contrast to previous research suggesting a central role for re-experiencing, emotional numbing and interpersonal avoidance in psychosis. Trauma-related beliefs were the psychological mechanism most associated with psychotic symptoms, although not all relevant mechanisms were measured. This work demonstrates that investigating multiple putative mediators may clarify which processes are most relevant to trauma-related psychosis. Further research should use network modelling to investigate how the spectrum of traumatic stress reactions play a role in psychotic symptoms.


Assuntos
Metanálise em Rede , Trauma Psicológico/psicologia , Transtornos Psicóticos/terapia , Transtornos de Estresse Pós-Traumáticos/terapia , Adulto , Ansiedade/psicologia , Delusões/etiologia , Feminino , Alucinações/etiologia , Humanos , Masculino , Estudo de Prova de Conceito , Psicoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Stat Appl Genet Mol Biol ; 18(3)2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30956231

RESUMO

Genome-wide sequencing enables evaluation of associations between traits and combinations of variants in genes and pathways. But such evaluation requires multi-locus association tests with good power, regardless of the variant and trait characteristics. And since analyzing families may yield more power than analyzing unrelated individuals, we need multi-locus tests applicable to both related and unrelated individuals. Here we describe such tests, and we introduce SKAT-X, a new test statistic that uses genome-wide data obtained from related or unrelated subjects to optimize power for the specific data at hand. Simulations show that: a) SKAT-X performs well regardless of variant and trait characteristics; and b) for binary traits, analyzing affected relatives brings more power than analyzing unrelated individuals, consistent with previous findings for single-locus tests. We illustrate the methods by application to rare unclassified missense variants in the tumor suppressor gene BRCA2, as applied to combined data from prostate cancer families and unrelated prostate cancer cases and controls in the Multi-ethnic Cohort (MEC). The methods can be implemented using open-source code for public use as the R-package GATARS (Genetic Association Tests for Arbitrarily Related Subjects) .


Assuntos
Estudos de Associação Genética/estatística & dados numéricos , Testes Genéticos , Software , Simulação por Computador , Variação Genética/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
10.
Cancer Sci ; 109(2): 435-445, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29247577

RESUMO

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.


Assuntos
Adenocarcinoma Mucinoso/genética , Consumo de Bebidas Alcoólicas/genética , Aldeído-Desidrogenase Mitocondrial/genética , Povo Asiático/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Razão de Chances
11.
Hum Mol Genet ; 25(17): 3863-3876, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27402876

RESUMO

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 2/genética , Elementos Facilitadores Genéticos , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Deleção de Sequência , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto Jovem
12.
Hum Mol Genet ; 25(12): 2612-2620, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27008869

RESUMO

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 6/genética , Neoplasias do Endométrio/patologia , Feminino , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , População Branca/genética
13.
BMC Cancer ; 18(1): 1072, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400783

RESUMO

BACKGROUND: The contribution of genetic polymorphisms to the large inter-individual variation in mammographic density (MD) changes following starting and stopping use of estrogen and progestin combined therapy (EPT) has not been well-studied. Previous studies have shown that circulating levels of insulin-like growth factors are associated with MD and cross-talk between estrogen signaling and growth factors is necessary for cell proliferation in the breast. We evaluated single nucleotide polymorphisms (SNPs) in growth factor genes in association with MD changes after women stop EPT use. METHODS: We genotyped 191 SNPs in 13 growth factor pathway genes in 284 non-Hispanic white California Teachers Study participants who previously used EPT and collected their mammograms before and after quitting EPT. Percent MD was assessed using a computer-assisted method. Change in percent MD was calculated by subtracting percent MD of an 'off-EPT' mammogram from percent MD of an 'on-EPT' (i.e. baseline) mammogram. We used multivariable linear regression analysis to investigate the association between SNPs and change in percent MD. We calculated P-values corrected for multiple testing within a gene (Padj). RESULTS: Rs1983210 in INHA and rs35539615 in IGFBP1/3 showed the strongest associations. Per minor allele of rs1983210, the absolute change in percent MD after stopping EPT use decreased by 1.80% (a difference in absolute change in percent MD) (Padj= 0.021). For rs35539615, change in percent MD increased by 1.79% per minor allele (Padj= 0.042). However, after applying a Bonferroni correction for the number of genes tested, these associations were no longer statistically significant. CONCLUSIONS: Genetic variation in growth factor pathway genes INHA and IGFBP1/3 may predict longitudinal MD change after women quit EPT. The observed differences in EPT-associated changes in percent MD in association with these genetic polymorphisms are modest but may be clinically significant considering that the magnitude of absolute increase in percent MD reported from large clinical trials of EPT ranged from 3% to 7%.


Assuntos
Densidade da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Inibinas/genética , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Adulto , Alelos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , California/epidemiologia , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/administração & dosagem , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos Longitudinais , Mamografia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Progestinas/administração & dosagem , População Branca/genética
14.
Br J Psychiatry ; 212(3): 180-182, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29436320

RESUMO

We present 12-month follow-up results for a randomised controlled trial of prolonged exposure and eye movement desensitisation and reprocessing (EMDR) therapy in 85 (78.8%) participants with psychotic disorder and comorbid post-traumatic stress disorder (PTSD). Positive effects on clinician-rated PTSD, self-rated PTSD, depression, paranoid-referential thinking and remission from schizophrenia were maintained up to 12-month follow-up. Negative post-traumatic cognitions declined in prolonged exposure and were stable in EMDR. A significant decline in social functioning was found, whereas reductions in interference of PTSD symptoms with social functioning were maintained. These results support that current PTSD guidelines apply to individuals with psychosis. Declaration of interest M.v.d.G. and D.v.d.B. receive income for published books on psychotic disorders and for the training of postdoctoral professionals in the treatment of psychotic disorders. A.d.J. receives income for published books on EMDR therapy and for the training of postdoctoral professionals in this method. A.v.M. receives income for published book chapters on PTSD and for the training of postdoctoral professionals in prolonged exposure. C.d.R. receives income for the training of postdoctoral professionals in EMDR therapy.


Assuntos
Dessensibilização e Reprocessamento através dos Movimentos Oculares/métodos , Terapia Implosiva/métodos , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/terapia , Esquizofrenia/terapia , Transtornos de Estresse Pós-Traumáticos/terapia , Adulto , Comorbidade , Seguimentos , Humanos , Transtornos Psicóticos/epidemiologia , Esquizofrenia/epidemiologia , Método Simples-Cego , Transtornos de Estresse Pós-Traumáticos/epidemiologia
15.
Int J Cancer ; 140(12): 2728-2733, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28295283

RESUMO

Genome-wide association studies (GWAS) in ethnic/racial minority populations can help to fine-map previously identified risk regions or discover new risk loci because of the genetic diversity in these populations. We conducted a GWAS of colorectal cancer (CRC) in 6,597 African Americans (1,894 cases and 4,703 controls) (Stage 1) and followed up the most promising markers in a replication set of 2,041 participants of African descent (891 cases and 1,150 controls) (Stage 2). We identified a novel variant, rs56848936 in the gene SYMPK at 19q13.3, associated with colon cancer risk (odds ratio 0.61 for the risk allele G, p = 2.4 × 10-8 ). The frequency of the G allele was 0.06 in African Americans, compared to <0.01 in Europeans, Asians and Amerindians in the 1000 Genomes project. In addition, a variant previously identified through fine-mapping in this GWAS in the region 19q13.1, rs7252505, was confirmed to be more strongly associated with CRC in the African American replication set than the variant originally reported in Europeans (rs10411210). The association between rs7252505 and CRC was of borderline significance (p = 0.05) in a Hispanic population GWAS with 1,611 CRC cases and 4,330 controls. With the three datasets combined, the odds ratio was 0.84 for the risk allele A (95% confidence interval 0.79-0.89, p = 3.7 × 10-8 ). This study further highlights the importance of conducting GWAS studies in diverse ancestry populations.


Assuntos
Neoplasias do Colo/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Negro ou Afro-Americano/genética , Idoso , Alelos , Povo Asiático/genética , Cromossomos Humanos Par 19/genética , Neoplasias do Colo/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Hispânico ou Latino/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fatores de Risco
16.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco , População Branca/genética
17.
Carcinogenesis ; 37(6): 547-556, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27207650

RESUMO

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Hispânico ou Latino/genética , Idoso , Alelos , Estudos de Coortes , Feminino , Variação Genética , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
18.
Hum Mol Genet ; 23(19): 5251-9, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24824216

RESUMO

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.


Assuntos
Alelos , Asma/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Asma/epidemiologia , Mapeamento Cromossômico , Feminino , Regulação da Expressão Gênica , Loci Gênicos , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Grupos Raciais/genética , Reprodutibilidade dos Testes , Fatores Sexuais
19.
Hum Mol Genet ; 23(5): 1387-98, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24163127

RESUMO

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Neoplasias da Bexiga Urinária/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Risco , Neoplasias da Bexiga Urinária/patologia
20.
PLoS Genet ; 9(3): e1003419, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555315

RESUMO

Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.


Assuntos
Neoplasias da Mama/genética , Éxons/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Negro ou Afro-Americano/genética , Idoso , Alelos , Asiático/genética , Neoplasias da Mama/patologia , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Fatores de Risco , População Branca
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