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1.
Biol Psychiatry Glob Open Sci ; 3(1): 110-118, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36712567

RESUMO

Background: Traumatic experiences are described as the strongest predictors of major depressive disorder (MDD), with inflammation potentially mediating the association between trauma and symptom onset. However, several studies indicate that body mass index (BMI) exerts a large confounding effect on both inflammation and MDD. Methods: First, we sought to replicate previously reported associations between these traits in a large subset of the UK Biobank, using regression models with C-reactive protein (CRP) and MDD and as the outcome variables in 113,481 and 30,137 individuals, respectively. Second, we ran bidirectional Mendelian randomization analyses between these traits to establish a potential causal framework between BMI, MDD, reported childhood trauma, and inflammation. Results: Our phenotypic analyses revealed no association between CRP and MDD but did suggest a strong effect of BMI and reported trauma on both CRP (BMI: ß = 0.43, 95% CI = 0.43-0.43, p ≤ .001; childhood trauma: ß = 0.02, 95% CI = 0.00-0.03, p = .006) and MDD (BMI: odds ratio [OR] = 1.16, 95% CI = 1.14-1.19, p ≤ .001; childhood trauma: OR = 1.99, 95% CI = 1.88-2.11, p ≤ .001). Our Mendelian randomization analyses confirmed a lack of causal relationship between CRP and MDD but showed evidence consistent with a strong causal influence of higher BMI on increased CRP (ß = 0.37, 95% CI = 0.36-0.39, p ≤ .001) and a bidirectional influence between reported trauma and MDD (OR trauma-MDD = 1.75, 95% CI = 1.49-2.07, p ≤ .001; OR MDD-trauma = 1.22, 95% CI = 1.18-1.27, p ≤ .001). Conclusions: Our findings highlight the importance of controlling for both BMI and trauma when studying MDD in the context of inflammation. They also suggest that the experience of traumatic events can increase the risk for MDD and that MDD can increase the experience of traumatic events.

2.
Am J Med Genet B Neuropsychiatr Genet ; 186(6): 389-398, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34658127

RESUMO

The requirement for large sample sizes for psychiatric genetic analyses necessitates novel approaches to derive cases. Anxiety and depression show substantial genetic overlap and share pharmacological treatments. Data on prescribed medication could be effective for inferring case status when other indicators of mental health are unavailable. We investigated self-reported current medication use in UK Biobank participants of European ancestry. Medication Status cases reported using antidepressant or anxiolytic medication (n = 22,218), controls did not report psychotropic medication use (n = 168,959). A subset, "Medication Only," additionally did not meet criteria for any other mental health indicator (case n = 2,643, control n = 107,029). We assessed genetic overlap between these phenotypes and two published genetic association studies of anxiety and depression, and an internalizing disorder trait derived from symptom-based questionnaires in UK Biobank. Genetic correlations between Medication Status and the three anxiety and depression phenotypes were significant (rg  = 0.60-0.73). In the Medication Only subset, the genetic correlation with depression was significant (rg  = 0.51). The three polygenic scores explained 0.33% - 0.80% of the variance in Medication Status and 0.07% - 0.19% of the variance in Medication Only. This study provides evidence that self-reported current medication use offers an alternate or supplementary anxiety or depression phenotype in genetic studies where diagnostic information is sparse or unavailable.


Assuntos
Bancos de Espécimes Biológicos , Depressão , Ansiedade/tratamento farmacológico , Ansiedade/genética , Depressão/tratamento farmacológico , Depressão/genética , Estudo de Associação Genômica Ampla , Humanos , Autorrelato , Reino Unido
3.
Commun Biol ; 4(1): 965, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446809

RESUMO

Despite the observed associations between psychiatric disorders and nutrient intake, genetic studies are limited. We examined whether polygenic scores for psychiatric disorders are associated with nutrient intake in UK Biobank (N = 163,619) using linear mixed models. We found polygenic scores for attention-deficit/hyperactivity disorder, bipolar disorder, and schizophrenia showed the highest number of associations, while a polygenic score for autism spectrum disorder showed no association. The relatively weaker obsessive-compulsive disorder polygenic score showed the greatest effect sizes suggesting its association with diet traits may become more apparent with larger genome-wide analyses. A higher alcohol dependence polygenic score was associated with higher alcohol intake and individuals with higher persistent thinness polygenic scores reported their food to weigh less, both independent of socioeconomic status. Our findings suggest that polygenic propensity for a psychiatric disorder is associated with dietary behaviour. Note, nutrient intake was self-reported and findings must therefore be interpreted mindfully.


Assuntos
Ingestão de Alimentos , Predisposição Genética para Doença/epidemiologia , Transtornos Mentais/epidemiologia , Herança Multifatorial , Distúrbios Nutricionais/epidemiologia , Fenótipo , Idoso , Idoso de 80 Anos ou mais , Animais , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/etiologia , Transtorno Bipolar/genética , Feminino , Predisposição Genética para Doença/etiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/genética , Pessoa de Meia-Idade , Distúrbios Nutricionais/etiologia , Distúrbios Nutricionais/genética , Esquizofrenia/epidemiologia , Esquizofrenia/etiologia , Esquizofrenia/genética , Reino Unido/epidemiologia
4.
Psychol Med ; 51(13): 2287-2297, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33583449

RESUMO

Enabled by advances in high throughput genomic sequencing and an unprecedented level of global data sharing, molecular genetic research is beginning to unlock the biological basis of eating disorders. This invited review provides an overview of genetic discoveries in eating disorders in the genome-wide era. To date, five genome-wide association studies on eating disorders have been conducted - all on anorexia nervosa (AN). For AN, several risk loci have been detected, and ~11-17% of the heritability has been accounted for by common genetic variants. There is extensive genetic overlap between AN and psychological traits, especially obsessive-compulsive disorder, and intriguingly, with metabolic phenotypes even after adjusting for body mass index (BMI) risk variants. Furthermore, genetic risk variants predisposing to lower BMI may be causal risk factors for AN. Causal genes and biological pathways of eating disorders have yet to be elucidated and will require greater sample sizes and statistical power, and functional follow-up studies. Several studies are underway to recruit individuals with bulimia nervosa and binge-eating disorder to enable further genome-wide studies. Data collections and research labs focused on the genetics of eating disorders have joined together in a global effort with the Psychiatric Genomics Consortium. Molecular genetics research in the genome-wide era is improving knowledge about the biology behind the established heritability of eating disorders. This has the potential to offer new hope for understanding eating disorder etiology and for overcoming the therapeutic challenges that confront the eating disorder field.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Estudo de Associação Genômica Ampla , Anorexia Nervosa/genética , Bulimia Nervosa/genética , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Genômica , Humanos , Biologia Molecular , Fenótipo
5.
Behav Genet ; 51(1): 58-67, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33141367

RESUMO

The relationship between genetic and environmental risk is complex and for many traits, estimates of genetic effects may be inflated by passive gene-environment correlation. This arises because biological offspring inherit both their genotypes and rearing environment from their parents. We tested for passive gene-environment correlation in adult body composition traits using the 'natural experiment' of childhood adoption, which removes passive gene-environment correlation within families. Specifically, we compared 6165 adoptees with propensity score matched non-adoptees in the UK Biobank. We also tested whether passive gene-environment correlation inflates the association between psychiatric genetic risk and body composition. We found no evidence for inflation of heritability or polygenic scores in non-adoptees compared to adoptees for a range of body composition traits. Furthermore, polygenic risk scores for anorexia nervosa, attention-deficit/hyperactivity disorder and schizophrenia did not differ in their influence on body composition traits in adoptees and non-adoptees. These findings suggest that passive gene-environment correlation does not inflate genetic effects for body composition, or the influence of psychiatric disorder genetic risk on body composition. Our design does not look at passive gene-environment correlation in childhood, and does not test for 'pure' environmental effects or the effects of active and evocative gene-environment correlations, where child genetics directly influences home environment. However, these findings suggest that genetic influences identified for body composition in this adult sample are direct, and not confounded by the family environment provided by biological relatives.


Assuntos
Composição Corporal/genética , Transtornos Mentais/genética , Adoção , Adulto , Criança Adotada , Bases de Dados Factuais , Bases de Dados Genéticas , Meio Ambiente , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Herança Multifatorial , Pais , Fatores de Risco , Reino Unido
6.
Psychol Sci ; 31(5): 582-591, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32302253

RESUMO

Polygenic scores now explain approximately 10% of the variation in educational attainment. However, they capture not only genetic propensity but also information about the family environment. This is because of passive gene-environment correlation, whereby the correlation between offspring and parent genotypes results in an association between offspring genotypes and the rearing environment. We measured passive gene-environment correlation using information on 6,311 adoptees in the UK Biobank. Adoptees' genotypes were less correlated with their rearing environments because they did not share genes with their adoptive parents. We found that polygenic scores were twice as predictive of years of education in nonadopted individuals compared with adoptees (R2s = .074 vs. .037, p = 8.23 × 10-24). Individuals in the lowest decile of polygenic scores for education attained significantly more education if they were adopted, possibly because of educationally supportive adoptive environments. Overall, these results suggest that genetic influences on education are mediated via the home environment.


Assuntos
Adoção , Bancos de Espécimes Biológicos , Escolaridade , Interação Gene-Ambiente , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Pais , Análise de Regressão , Reino Unido
7.
Int J Eat Disord ; 52(11): 1205-1223, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512774

RESUMO

OBJECTIVE: Clinically, anorexia nervosa (AN) presents with altered body composition. We quantified these alterations and evaluated their relationships with metabolites and hormones in patients with AN longitudinally. METHOD: In accordance with PRISMA guidelines, we conducted 94 meta-analyses on 62 samples published during 1996-2019, comparing up to 2,319 pretreatment, posttreatment, and weight-recovered female patients with AN with up to 1,879 controls. Primary outcomes were fat mass, fat-free mass, body fat percentage, and their regional distribution. Secondary outcomes were bone mineral density, metabolites, and hormones. Meta-regressions examined relationships among those measures and moderators. RESULTS: Pretreatment female patients with AN evidenced 50% lower fat mass (mean difference [MD]: -8.80 kg, 95% CI: -9.81, -7.79, Q = 1.01 × 10-63 ) and 4.98 kg (95% CI: -5.85, -4.12, Q = 1.99 × 10-28 ) lower fat-free mass, with fat mass preferentially stored in the trunk region during early weight restoration (4.2%, 95% CI: -2.1, -6.2, Q = 2.30 × 10-4 ). While the majority of traits returned to levels seen in healthy controls after weight restoration, fat-free mass (MD: -1.27 kg, 95% CI: -1.79, -0.75, Q = 5.49 × 10-6 ) and bone mineral density (MD: -0.10 kg, 95% CI: -0.18, -0.03, Q = 0.01) remained significantly altered. DISCUSSION: Body composition is markedly altered in AN, warranting research into these phenotypes as clinical risk or relapse predictors. Notably, the long-term altered levels of fat-free mass and bone mineral density suggest that these parameters should be investigated as potential AN trait markers. RESUMENOBJETIVO: Clínicamente, la anorexia nervosa (AN) se presenta con alteraciones en la composición corporal. Cuantificamos estas alteraciones y evaluamos longitudinalmente su relación con metabolitos y hormonas en pacientes con AN. MÉTODO: De acuerdo con las pautas PRISMA, realizamos 94 meta-análisis en 62 muestras publicadas entre 1996-2019, comparando hasta 2,319 pacientes mujeres en pre-tratamiento, post-tratamiento, y recuperadas en base al peso con hasta 1,879 controles. Las principales medidas fueron masa grasa, masa libre de grasa, porcentaje de grasa corporal y su distribución regional. Las medidas secundarias fueron densidad mineral ósea, metabolitos y hormonas. Las meta-regresiones examinaron las relaciones entre esas medidas y moderadores. RESULTADOS: Las pacientes femeninas con AN pre-tratamiento mostraron un 50% menos de masa grasa (MD: -8.80 kg, CI 95%: -9.81, -7.79, Q = 1.01 × 10-63 ) y 4.98 kg (CI 95%: -5.85, -4.12, Q = 1.99 × 10-28 ) menos de masa libre de grasa, con masa grasa preferentemente almacenada en la región del tronco durante la recuperación temprana del peso (4.2%, CI 95%: -2.1, -6.2, Q = 2.30 × 10-4 ). Aunque la mayoría de los rasgos regresaron a los niveles vistos en los controles sanos después de la restauración del peso, la masa libre de grasa (MD: -1.27 kg, CI 95%: -1.79, -0.75, Q = 5.49 × 10-6 ) y la densidad mineral ósea (MD: -0.10 kg, CI 95%: -0.18, -0.03, Q = 0.01) permanecieron significativamente alteradas. DISCUSIÓN: La composición corporal es marcadamente alterada en la AN, lo que garantiza la investigación en estos fenotipos como predictores de riesgo clínico o de recaída. Notablemente, la alteración a largo plazo de los niveles de masa libre de grasa y densidad mineral ósea sugieren que estos parámetros debe ser investigados como potenciales rasgos indicadores de AN.


Assuntos
Anorexia Nervosa/diagnóstico , Composição Corporal/fisiologia , Estudos Transversais , Humanos , Estudos Longitudinais
8.
Stem Cells Transl Med ; 7(5): 439-449, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29489062

RESUMO

Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC-MSCs (ES-MSCs from embryonic stem cells) to fetal MSCs (AF-MSCs from the amniotic fluid), demonstrating that ES-MSCs have a superior neuroprotective potential over AF-MSCs in the mouse brain following hypoxia-ischemia. Further, we demonstrate that nuclear factor (NF)-κB-stimulated interleukin (IL)-13 production contributes to an increased in vitro anti-inflammatory potential of ES-MSC-conditioned medium (CM) over AF-MSC-CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell-derived MSCs (iMSCs) exhibit many similarities to ES-MSCs, including enhanced NF-κB signaling and IL-13 production in comparison to AF-MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES-MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic-ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439-449.


Assuntos
Encéfalo/patologia , Células-Tronco Embrionárias/citologia , Células-Tronco Fetais/citologia , Hipóxia/patologia , Células-Tronco Mesenquimais/citologia , Neuroproteção/fisiologia , Líquido Amniótico/citologia , Animais , Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Células-Tronco Embrionárias/metabolismo , Feminino , Células-Tronco Fetais/metabolismo , Células HEK293 , Humanos , Hipóxia/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Isquemia/metabolismo , Isquemia/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Medicina Regenerativa/métodos , Transdução de Sinais/fisiologia
9.
Sci Rep ; 8(1): 2425, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402914

RESUMO

Human amniotic fluid contains two morphologically-distinct sub-populations of stem cells with regenerative potential, spindle-shaped (SS-hAFSCs) and round-shaped human amniotic fluid stem cells (RS-hAFSCs). However, it is unclear whether morphological differences correlate with functionality, and this lack of knowledge limits their translational applications. Here, we show that SS-hAFSCs and RS-hAFSCs differ in their neuro-protective ability, demonstrating that a single contralateral injection of SS-hAFSCs into hypoxic-ischemic P7 mice conferred a 47% reduction in hippocampal tissue loss and 43-45% reduction in TUNEL-positive cells in the hippocampus and striatum 48 hours after the insult, decreased microglial activation and TGFß1 levels, and prevented demyelination. On the other hand, RS-hAFSCs failed to show such neuro-protective effects. It is possible that SS-hAFSCs exert their neuroprotection via endoglin-dependent inhibition of TGFß1 signaling in target cells. These findings identify a sub-population of CD117+CD90+CD105+ stem cells as a promising source for the neuro-protection of the developing brain.


Assuntos
Líquido Amniótico/citologia , Isquemia Encefálica/terapia , Doenças Desmielinizantes/prevenção & controle , Hipóxia/prevenção & controle , Neuroproteção/fisiologia , Transplante de Células-Tronco , Células-Tronco/citologia , Líquido Amniótico/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptose , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Linhagem da Célula , Terapia Baseada em Transplante de Células e Tecidos/métodos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Endoglina/genética , Endoglina/metabolismo , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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