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1.
J Trauma Stress ; 34(3): 607-615, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33529416

RESUMO

Emerging research has demonstrated that psychosocial trauma exposure may elicit epigenetic changes, with downstream effects on the transcriptional regulation of genes. Epigenome-wide association studies (EWAS) offer an agnostic approach to examine DNA methylation (DNAm) associations and are a valuable tool to aid in the identification of biological pathways involved in posttraumatic stress disorder (PTSD). This study represents the first EWAS of PTSD in an adolescent sample, an important group given the significance of this developmental period regarding both DNAm changes and PTSD risk. The sample (n = 39, M age = 15.41 years, SD = 1.27, 84.6% female) comprised adolescents who experienced interpersonal trauma and were enrolled in a treatment study. Participants were assessed using the UCLA PTSD Reaction Index for DSM-IV-Adolescent Version and provided a blood sample at baseline. Genomic DNA was isolated from whole blood and assayed using the Illumina Infinium MethylationEPIC BeadChip. The primary analysis estimated the associations among individual CpG sites and PTSD symptom scores. Of the 793,575 screened probes tested, two were significant at a false discovery rate (FDR) < 10%. Hypomethylation of both sites was associated with increased PTSD symptom scores. Analysis of differentially methylated regions (DMR) identified a DMR associated with PTSD symptom scores at an FDR < 10%. Results from follow-up models are also discussed. Findings from this preliminary investigation suggest the importance of further research conducted in adolescent samples. The analytic pipeline and results are documented for use in future meta-analytic work as more such samples become available.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Adolescente , Metilação de DNA/genética , Epigênese Genética , Epigenoma , Feminino , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/genética
2.
J Perinat Neonatal Nurs ; 35(1): 4-7, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33528179

RESUMO

Depression onset during and after pregnancy is prevalent and associated with significant implications for maternal, child, and family health. Although environmental risk factors important to the expression of pregnancy-related depression are well known, knowledge of the genetic underpinning is limited. Given the joint contribution of environmental and genetic factors to depression risk liability, DNA methylation presents itself as an ideal biomarker to investigate basic mechanisms and opportunities for translational research to care for pregnancy-related depression health outcomes. This article is an introduction to DNA methylation and its potential to serve as a marker of depression risk during pregnancy and the postpartum. This commentary discusses current clinical uses of DNA methylation-based testing and how it may be applied to perinatal depression clinical care and management.


Assuntos
Metilação de DNA , Depressão Pós-Parto/metabolismo , Precursores de Proteínas/metabolismo , Adulto , Depressão Pós-Parto/genética , Feminino , Humanos , Comportamento Materno , Assistência Perinatal , Gravidez , Receptores de Ocitocina/metabolismo
3.
Nurs Res ; 69(1): 82-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31373995

RESUMO

BACKGROUND: Pregnant women with depressive symptoms face significant treatment challenges and are in great need of safe, effective, accessible, inexpensive, and nonpharmacological self-management therapies to enhance well-being, reduce the burden of symptoms both during their pregnancy and postpartum, and prevent chronic sequelae. OBJECTIVES: In this article, we describe the protocol for our pilot study testing a self-management intervention entitled, "Mindful Moms," designed to foster women's ability to address current depressive symptoms and enhance resilience to prevent recurrence. METHODS: We will conduct a longitudinal pilot trial of the 12-week intervention with pregnant women with depressive symptoms (n = 40); the primary aim is to determine the feasibility and acceptability of the intervention. The secondary aim is to examine preliminary effects of the intervention on maternal psychobehavioral outcomes in pregnancy and 6 weeks postpartum. The third aim will quantify genome-wide and gene-specific DNA methylation patterns associated with depressive symptoms during pregnancy and investigate whether intervention participation influences these patterns. RESULTS: This study is currently ongoing. DISCUSSION: Findings from this study will inform future research addressing the need for nonpharmacological self-management interventions for pregnant women with depressive symptoms.


Assuntos
Transtorno Depressivo/prevenção & controle , Complicações na Gravidez/psicologia , Complicações na Gravidez/terapia , Gestantes/psicologia , Autogestão/métodos , Adulto , Feminino , Humanos , Estudos Longitudinais , Projetos Piloto , Gravidez , Projetos de Pesquisa
4.
J Child Psychol Psychiatry ; 60(9): 1032-1041, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30994196

RESUMO

BACKGROUND: Little is known about genetic and environmental influences on the components of disruptive mood dysregulation disorder (DMDD), tonic irritability (i.e., irritable mood) and phasic irritability (i.e., temper outbursts). This study examined prevalence, stability, and heritability of tonic irritability, phasic irritability, and a DMDD proxy (pDMDD) based on DSM-5 criteria. METHODS: pDMDD was derived using data from clinical interviews of parents and their twins (N = 1,431 twin pairs), ages 8-17, participating in Waves 1 and 2 of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical modeling was used to compare a common pathway model (CPM) and an independent pathway model (IPM), and heritability estimates were obtained for pDMDD using the symptoms of irritable mood (tonic irritability; DMDD Criterion D), intense temper outbursts (phasic irritability; DMDD Criterion A), and frequent temper outbursts (phasic irritability; DMDD Criterion C). RESULTS: Lifetime prevalence of pDMDD was 7.46%. The stability of DMDD symptoms and the pDMDD phenotype across approximately one year were moderate (.30-.69). A CPM was a better fit to the data than an IPM. Phasic irritability loaded strongly onto the pDMDD latent factor (.89-.96) whereas tonic irritability did not (.28). Genetic influences accounted for approximately 59% of the variance in the latent pDMDD phenotype, with the remaining 41% of the variance due to unique environmental effects. The heritability of tonic irritability (54%) was slightly lower than that of frequent and intense temper (components of phasic irritability; 61% and 63%, respectively). CONCLUSIONS: Compared to tonic irritability, phasic irritability appears to be slightly more stable and heritable, as well as a stronger indicator of the latent factor. Furthermore, environmental experiences appear to play a substantial role in the development of irritability and DMDD, and researchers should seek to elucidate these mechanisms in future work.


Assuntos
Comportamento do Adolescente , Sintomas Afetivos , Comportamento Infantil , Predisposição Genética para Doença , Humor Irritável , Transtornos do Humor , Comportamento Problema , Adolescente , Comportamento do Adolescente/fisiologia , Sintomas Afetivos/epidemiologia , Sintomas Afetivos/genética , Sintomas Afetivos/fisiopatologia , Criança , Comportamento Infantil/fisiologia , Feminino , Humanos , Humor Irritável/fisiologia , Estudos Longitudinais , Masculino , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Prevalência
5.
J Behav Med ; 42(5): 911-923, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30671916

RESUMO

Robust associations between adverse childhood experiences and shortened telomere length exist, but few studies have examined factors that may moderate this association, particularly with a resilience framework. The present study examined the association between exposure to childhood sexual abuse (and abuse severity) and mean telomere length, and whether social support and optimism moderated this association. The sample included 99 White monozygotic female twins, ranging in age from 35 to 70 (Mage = 52.74, SD = 8.55 years), who provided a blood sample for telomere assay, and data on their childhood sexual abuse history, trait optimism, and current social support. Linear mixed effects models were employed to test study hypotheses. There were no effects of exposure to abuse or abuse severity on mean telomere length, nor were there main or moderating effects of optimism, in analyses of the full sample. However, in analyses that only included women exposed to abuse, there was an abuse type × support interaction: among women who experienced abuse in forms other than intercourse, higher levels of social support were associated with longer mean telomere length. Findings from the current study clarify the role of childhood sexual abuse in telomere attrition, and identify one factor that may protect against the negative biological effects of childhood sexual abuse.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/estatística & dados numéricos , Abuso Sexual na Infância/estatística & dados numéricos , Otimismo/psicologia , Apoio Social , Encurtamento do Telômero , Adulto , Idoso , Criança , Feminino , Humanos , Pessoa de Meia-Idade , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/psicologia , Adulto Jovem
6.
Soc Psychiatry Psychiatr Epidemiol ; 54(5): 639-647, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30003310

RESUMO

PURPOSE: Posttraumatic stress disorder (PTSD) often co-occurs with panic disorder (PD), with some etiological models positing a causal role of panic reactivity in PTSD onset; however, data addressing the temporal ordering of these conditions are lacking. The aim of this study was to examine the bi-directional associations between PD and PTSD in a nationally representative, epidemiologic sample of trauma-exposed adults. METHODS: Participants were community-dwelling adults (62.6% women; Mage = 48.9, SD 16.3) with lifetime DSM-IV PTSD criterion A trauma exposure drawn from the 2001/2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and re-interviewed in 2004/5 (N = 12,467). Cox discrete-time proportional hazards models with time-varying covariates were used to investigate the bi-directional associations between lifetime PD and PTSD, accounting for demographic characteristics, trauma load, and lifetime history of major depression, generalized anxiety disorder, and social anxiety disorder. RESULTS: PD was significantly associated with subsequent onset of PTSD (HR 1.210, 95%CI = 1.207-1.214, p < .001), and PTSD was significantly associated with onset of PD (HR 1.601, 95% CI 1.597-1.604, p < .001). The association between PTSD and subsequent PD was stronger in magnitude than that between PD and subsequent PTSD (Z = - 275.21, p < .01). Men evidenced stronger associations between PD and PTSD compared to women. CONCLUSIONS: Results were consistent with a bidirectional pathway of risk, whereby PD significantly increased risk for the development of PTSD, and PTSD significantly increased risk for PD. Given the association between PTSD and subsequent PD, particularly among men, clinicians may consider supplementing PTSD treatment with panic-specific interventions, such as interoceptive exposure, to prevent or treat this disabling comorbidity.


Assuntos
Transtorno de Pânico/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Fatores de Tempo , Adulto , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/psicologia , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/psicologia , Estados Unidos/epidemiologia
7.
Biol Reprod ; 98(3): 309-322, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29324974

RESUMO

Gestational choriocarcinomas are derived from placental trophoblast cells, with HLA-C being the only class I polymorphic molecule expressed. However, choriocarcinomas have not been profiled for endoplasmic reticulum aminopeptidase 2 (ERAP2) expression. ERAP2 trims peptides presented by human leukocyte antigens (HLA) that have shown to modulate immune response. Over 50% of choriocarcinomas we screened lack ERAP2 expression, which suggests that the absence of ERAP2 expression allows immune evasion of choriocarcinoma cells. We demonstrate that the ability of choriocarcinoma cells to activate lymphocytes was lowest with cells lacking ERAP2 (JEG-3) or HLA-C (JAr). This observation suggests that activation is dependent on expression of both ERAP2 and HLA-C molecules. In addition, an ERAP2 variant in which lysine is changed to asparagine (K392N) results in increased trimming activity (165-fold) for hydrophobic peptides and biologically never been detected. We hypothesize that homozygosity for the N392 ERAP2 variant is prohibited because it modulates the immune recognition of placental trophoblasts. We demonstrate that NK-cell activation and killing were significantly dependent on forced expression of the N392 ERAP2 isoform in JEG-3 cells. Cytotoxicity was confirmed by 7AAD killing assays showing that N392 ERAP2-isoform expressing JEG-3 cells had the highest percentage of apoptotic cells independent of the expression level of CD11a on lymphocytes. This is the first report showing that N392 ERAP2 promotes an immune clearance pathway for choriocarcinoma cells, and provides an explanation for why embryonic homozygosity for the N392 ERAP2 variant is not detected in any population.


Assuntos
Aminopeptidases/metabolismo , Coriocarcinoma/imunologia , Neoplasias do Colo do Útero/imunologia , Linhagem Celular Tumoral , Coriocarcinoma/metabolismo , Feminino , Humanos , Interferon gama/farmacologia , Gravidez , Trofoblastos/efeitos dos fármacos , Trofoblastos/imunologia , Trofoblastos/metabolismo , Neoplasias do Colo do Útero/metabolismo
8.
BMC Med Genet ; 19(1): 181, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30290772

RESUMO

BACKGROUND: Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed. METHODS: We developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations. RESULTS: We describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene. CONCLUSIONS: Our findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.


Assuntos
População Negra , Códon sem Sentido , Ruptura Prematura de Membranas Fetais/genética , Predisposição Genética para Doença , Lectina de Ligação a Manose/genética , Nascimento Prematuro/genética , beta-Defensinas/genética , Adulto , Alelos , Proteínas de Transporte/genética , Estudos de Casos e Controles , Feminino , Ruptura Prematura de Membranas Fetais/etnologia , Ruptura Prematura de Membranas Fetais/patologia , Feto , Expressão Gênica , Frequência do Gene , Genoma Humano , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Polimorfismo de Nucleotídeo Único , Gravidez , Nascimento Prematuro/etnologia , Nascimento Prematuro/patologia , Sequenciamento do Exoma
9.
Am J Obstet Gynecol ; 218(3): 294-314.e2, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29248470

RESUMO

Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing-identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes that contribute to preterm birth by whole exome sequencing, or whole genome sequencing, promises to yield valuable population-specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk.


Assuntos
Sequenciamento do Exoma , Predisposição Genética para Doença , Inflamação/genética , Nascimento Prematuro/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Inflamação/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Periodontais/genética , Gravidez , Nascimento Prematuro/etiologia
10.
J Genet Couns ; 27(5): 1157-1166, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29460111

RESUMO

Huntington disease (HD) is a progressive neurodegenerative disorder. Presymptomatic genetic testing allows at-risk individuals to clarify their risk status. Understanding the characteristics and motivations of individuals seeking HD presymptomatic genetic testing better equips genetic counselors and other healthcare professionals to provide comprehensive and personalized care. The aims of this study were to (1) determine whether the average age when individuals seek presymptomatic HD genetic testing has decreased over time, (2) assess motivations for seeking testing, (3) explore whether there is a relationship between age and motivations, and (4) explore genetic counselors' perceptions of the shift in age. Data from the US HD testing centers (N = 4) were analyzed. A small but statistically significant decrease in age of individuals seeking presymptomatic testing was observed (p = 0.045). HD community members (N = 77) were surveyed regarding presymptomatic testing motivations. Younger individuals were more likely than older individuals to cite "To learn whether or not you would develop HD" and "To make choices about further education or a career" compared to older individuals (p < 0.05). Conversely, older individuals more frequently cited "To give children a better idea of their risk" (p < 0.002). Sixteen percent of genetic counselors surveyed (6/37) perceived a change in age of testing. All of these respondents had provided HD testing for ten or more years and anecdotally believed the age at testing has decreased over time. Study results help providers personalize counseling based on patient's age and serve as a starting point for more research into the relationship between age at testing and motivations for testing.


Assuntos
Testes Genéticos/métodos , Doença de Huntington/genética , Adulto , Idoso , Feminino , Aconselhamento Genético , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/psicologia , Masculino
11.
Dev Psychobiol ; 60(2): 127-139, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29344930

RESUMO

Maternal prenatal stress has been linked to a variety of infant postnatal outcomes, partially through alterations in fetal HPA axis functioning; yet the underlying pathobiology remains elusive. Current literature posits DNA methylation as a candidate mechanism through which maternal prenatal stress can influence fetal HPA axis functioning. The goal of this systematic review was to summarize the literature examining the associations among maternal prenatal stress, DNA methylation of commonly studied HPA axis candidate genes, and infant HPA axis functioning. Results from the review provided evidence for a link between various maternal prenatal stressors, NR3C1 methylation, and infant stress reactivity, but findings among other genes were limited, with mixed results. An original study quality review tool revealed that a majority of studies in the review are adequate, and emphasizes the need for future research to consider study quality when interpreting research findings.


Assuntos
Metilação de DNA/fisiologia , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Metilação de DNA/genética , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactente , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
12.
Child Psychiatry Hum Dev ; 49(1): 33-41, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28488144

RESUMO

This study examined the effect of parenting on the association between childhood sexual abuse (CSA) and psychiatric resilience in adulthood in a large female twin sample (n = 1423) assessed for severe CSA (i.e., attempted or completed intercourse before age 16). Severe CSA was associated with lower resilience to recent stressors in adulthood (defined as the difference between their internalizing symptoms and their predicted level of symptoms based on cumulative exposure to stressful life events). Subscales of the Parental Bonding Instrument were significantly associated with resilience. Specifically, parental warmth was associated with increased resilience while parental protectiveness was associated with decreased resilience. The interaction between severe CSA and parental authoritarianism was significant, such that individuals with CSA history and higher authoritarianism scores had lower resilience. Results suggest that CSA assessment remains important for therapeutic work in adulthood and that addressing parenting may be useful for interventions in children with a CSA history.


Assuntos
Abuso Sexual na Infância/psicologia , Relações Pais-Filho , Poder Familiar/psicologia , Pais/psicologia , Resiliência Psicológica , Adolescente , Adulto , Criança , Educação Infantil/psicologia , Feminino , Humanos , Apego ao Objeto , Gêmeos/psicologia , População Branca
13.
Alcohol Clin Exp Res ; 40(6): 1328-38, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27155784

RESUMO

BACKGROUND: The relationship between gestational age at birth (GA) and alcohol use measures in early adulthood was examined in a large U.K. community-based birth cohort (Avon Longitudinal Study of Parents and Children). METHODS: A series of linear and logistic regression models were used to test for main effects of a continuous measure of GA on a range of alcohol use measures, and moderation of these associations by sex. In addition, mediation analyses assessed the extent to which significant associations between GA and alcohol use operated indirectly, through influences of the parental environment and/or childhood measures of emotional and behavioral health (EBH). RESULTS: Earlier GA significantly predicted never drinking by age 18, but was not associated with other measures of alcohol use behavior among young adult drinkers (i.e., Self-Rating of the Effects of Alcohol, Alcohol Use Disorders Identification Test, or DSM-IV-TR Criteria for Alcohol Dependence). The association between earlier GA and never drinking by age 18 was moderated by sex, such that females born early were less likely to have ever had a drink by age 18. In the full sample, childhood measures of EBH were found to mediate the association between earlier GA and never drinking by age 18. This association was not mediated by parenting factors. CONCLUSIONS: Earlier GA is associated with never drinking alcohol in early adulthood, in females. Emotional and behavioral difficulties experienced in early childhood may mediate the relationship between earlier GA and never drinking by age 18.


Assuntos
Sintomas Afetivos/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Idade Gestacional , Adolescente , Adulto , Fatores Etários , Feminino , Humanos , Estudos Longitudinais , Masculino , Comportamento Problema/psicologia , Fatores Sexuais , Reino Unido/epidemiologia , Adulto Jovem
14.
Behav Genet ; 44(5): 445-55, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25060210

RESUMO

Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype ("maternal effects", M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ~4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Locos de Características Quantitativas , Genótipo , Fenótipo , Característica Quantitativa Herdável
15.
Am J Obstet Gynecol ; 210(5): 398-405, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24096276

RESUMO

This review describes how improvements in biometric-genetic studies of twin kinships, half-sibships, and cousinships have now demonstrated a sizeable fetal genetic and maternal genetic contribution to the spontaneous onset of labor. This is an important development because previous literature for the most part reports only an influence of the maternal genome. Current estimates of the percent of variation that is attributable to fetal genetic factors range from 11-35%; the range for the maternal genetic contribution is 13-20%. These same studies demonstrate an even larger influence of environmental sources over and above the influence of genetic sources and previously identified environmental risk factors. With these estimates in hand, a major goal for research on pregnancy duration is to identify specific allelic variation and environmental risk to account for this estimated genetic and environmental variation. A review of the current literature can serve as a guide for future research efforts.


Assuntos
Idade Gestacional , Início do Trabalho de Parto/fisiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/fisiopatologia , Meio Ambiente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Início do Trabalho de Parto/genética , Epidemiologia Molecular , Gravidez , Resultado da Gravidez/epidemiologia , Resultado da Gravidez/genética , Nascimento Prematuro/genética , Fatores de Risco
16.
medRxiv ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38946966

RESUMO

People with mosaicism for trisomy 21 have been shown to exhibit the many of same phenotypic traits present in people with non-mosaic Down syndrome, but with varying symptom severity. However, the behavioral phenotype of people with mosaic Down syndrome (mDS) has not been well characterized. This study aimed to examine the prevalence of self-report and caregiver-report symptoms of depression and anxiety among a sample of 62 participants with mDS aged 12 - 46, and assess their association with the percentage of trisomy 21 in blood and/or buccal mucosa cells. The results showed that 53% of the participants reported clinically significant depression symptoms and 76% reported clinically significant anxiety symptoms. No clear associations were observed between the percentage of trisomic cells and total anxiety or depression, but a significant positive association between the proband-reported specific fears subscale and the percentage of trisomic cells in buccal specimens was detected (r = .43, p = .007). This study highlights the high occurrence of depression and anxiety symptoms in individuals with mDS and the need for routine assessment to optimize their care. It also demonstrates the ability of people with mDS to complete these evaluations, thereby supporting their inclusion in research studies/clinical trials.

17.
Am J Epidemiol ; 178(4): 543-50, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23568591

RESUMO

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.


Assuntos
Idade Gestacional , Resultado da Gravidez/genética , Nascimento Prematuro/genética , Gêmeos/genética , Declaração de Nascimento , Feminino , Feto , Fenômenos Genéticos , Humanos , Recém-Nascido , Masculino , Mães , Gravidez , Suécia
18.
Gene ; 852: 147062, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36423778

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. We report significant association of androgen production with 15 single nucleotide variants (SNVs) identified by exome sequencing of theca cells from women with PCOS and normal ovulatory women. Ten SNVs are located within a 150 kbp region on 12q13.2 which encompasses loci identified in PCOS genome-wide association studies (GWAS) and contains PCOS candidate genes ERBB3 and RAB5B. The region also contains PA2G4 which encodes a transcriptional corepressor of androgen receptor and androgen receptor-regulated genes. PA2G4 has not previously been recognized as related to PCOS in published GWAS studies. Two of the SNVs are predicted to have functional consequences (ERBB3 missense SNV, PA2G4 promoter SNV). PA2G4 interacts with the ERBB3 cytoplasmic domain containing the missense variant, suggesting a potential signaling pathway disruption that could lead to the PCOS ovarian phenotype. Single cell RNA sequencing of theca cells showed significantly less expression of PA2G4 after forskolin treatment in PCOS cells compared to normal cells (padj = 3.82E-30) and in cells heterozygous for the PA2G4 promoter SNV compared to those without the SNV (padj = 2.16E-11). This is consistent with a functional effect of the PA2G4 promoter SNV. No individual SNV was significantly associated with PCOS in an independent family cohort, but a haplotype with minor alleles of three SNVs was found preferentially in women with PCOS. These findings suggest a functional role for 12q13.2 variants in PCOS and implicate variants in ERBB3 and PA2G4 in the pathophysiology of PCOS.


Assuntos
Hiperandrogenismo , Síndrome do Ovário Policístico , Proteínas de Ligação a RNA , Receptor ErbB-3 , Proteínas rab5 de Ligação ao GTP , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos/metabolismo , Estudo de Associação Genômica Ampla , Hiperandrogenismo/genética , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Receptor ErbB-3/genética , Receptores Androgênicos/genética , Proteínas de Ligação a RNA/genética , Proteínas rab5 de Ligação ao GTP/genética
19.
Reprod Sci ; 30(7): 2025-2039, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36781584

RESUMO

A history of abortion is associated with cervical dysfunction during pregnancy, but there remains uncertainty about whether risk can be stratified by the abortion type, the abortion procedure, or number of previous abortions. The objective of this study was to verify the relationship between cervical dysfunction measures in pregnancies with and without a history of termination. Embase and Medline databases were searched from 01 January 1960 to 01 March 2022 resulting in a full-text review of 28 studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality and risk of bias for non-randomized studies. The meta-analysis consisted of 6 studies that met all inclusion and exclusion criteria and included a combined total of 2,513,044 pregnancies. Cervical dysfunction was defined as either cervical insufficiency/incompetence in 4 of the studies and as short cervix in the others. Results from a random-effects model using reported adjusted odds ratios (aOR) estimated an increase in the odds of 2.71 (95% CI 1.76, 4.16) for cervical dysfunction in the current pregnancy related to a history of induced or spontaneous abortion. Subgroup analyses with only induced abortions (surgical/medical) estimated an aOR of 2.54 (95% CI 1.41, 4.57), while studies limited to surgical abortions had an aOR of 4.08 (95% CI 2.84, 5.86). The risk of cervical dysfunction in the current pregnancy was also found to be dependent on the number of previous abortions. In this meta-analysis, a prior history of abortion, and specifically induced abortions, was associated with cervical dysfunction. The protocol was registered in PROSPERO (CRD42020209723).


Assuntos
Aborto Induzido , Aborto Espontâneo , Incompetência do Colo do Útero , Gravidez , Feminino , Humanos , Gestantes , Colo do Útero , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Fatores de Risco
20.
Mutat Res ; 747(2): 207-17, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22613870

RESUMO

The frequency of spontaneously occurring micronuclei (MN) increases with age, with many of these MN containing sex chromatin. However, it is not known if this MN frequency increase is attributable to a higher number of the same cellular events that occur in younger people, or if a different sex chromosomal instability mechanism(s) arises with age. To gain insight regarding this question, the total number of signals present in MN and their corresponding binucleates, was scored in older (ages 40-80+ y.o.; n=40) compared to younger (7-39 y.o.; n=19) individuals using probes specific for the X and Y chromosomes. In 19.9% of the cells scored at least one sex chromatin positive micronucleus was present. A significant decrease in cells having a "corrective" loss pattern (i.e. trisomy rescue, leading to euploid binucleates following sex chromatin exclusion into the MN) was observed with increasing age for the Y chromosome in males (p=0.022) and the X chromosome in females (p=0.004). In addition, a significant increase (p<0.001) in cells having multiple signals beyond those expected from a single cellular error was observed in the older compared to younger study participants, with these imbalances resulting from cells having either a single micronucleus with multiple signals, or cells having multiple MN. Collectively, these findings suggest that age-related increases in MN frequencies reflect both gains in the occurrence of similar cellular errors, as well as changes in the types of chromosomal findings that occur. Importantly, these results also illustrate that while MN frequencies reflect acquired abnormalities, they may also reflect cellular responses to "correct" an error, particularly when evaluated in young individuals. Therefore, when analyzing MN frequencies, one may also wish to evaluate the imbalances present in both the binucleates and MN to facilitate the recognition of varying cellular responses to environmental or genotoxic exposures.


Assuntos
Micronúcleos com Defeito Cromossômico , Cromossomos Sexuais , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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