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1.
Cereb Cortex ; 31(1): 681-693, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32959054

RESUMO

The neurobiology of heterogeneous neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) is still unknown. We hypothesized that differences in subject-level properties of intrinsic brain networks were important features that could predict individual variation in ASD symptom severity. We matched cases and controls from a large multicohort ASD dataset (ABIDE-II) on age, sex, IQ, and image acquisition site. Subjects were matched at the individual level (rather than at group level) to improve homogeneity within matched case-control pairs (ASD: n = 100, mean age = 11.43 years, IQ = 110.58; controls: n = 100, mean age = 11.43 years, IQ = 110.70). Using task-free functional magnetic resonance imaging, we extracted intrinsic functional brain networks using projective non-negative matrix factorization. Intrapair differences in strength in subnetworks related to the salience network (SN) and the occipital-temporal face perception network were robustly associated with individual differences in social impairment severity (T = 2.206, P = 0.0301). Findings were further replicated and validated in an independent validation cohort of monozygotic twins (n = 12; 3 pairs concordant and 3 pairs discordant for ASD). Individual differences in the SN and face-perception network are centrally implicated in the neural mechanisms of social deficits related to ASD.

2.
Mol Psychiatry ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144709

RESUMO

The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan-kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.

3.
Public Health Nutr ; : 1-13, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33040772

RESUMO

OBJECTIVE: To evaluate the hypothesis that a perinatal educational dietary intervention focused on 'eating for the gut microbiota' improves diet quality of pregnant women pre- and postnatally. DESIGN: The Healthy Parents, Healthy Kids study is a prospectively registered randomised controlled trial designed to evaluate the efficacy of a dietary intervention in altering the maternal and infant gut microbiota and improving perinatal diet quality. Eligible pregnant women were randomised to receive dietary advice from their healthcare provider or to additionally receive a three session dietary intervention. Dietary data were collected at gestation weeks 26, 31, 36 and postnatal week 4. Outcome measures were diet quality, dietary variety, prebiotic and probiotic food intakes, energy, fibre, saturated fat and discretionary food intakes. Between-group differential changes from baseline before and after birth in these dietary measures were assessed using generalised estimating equations. SETTING: Melbourne, Australia. PARTICIPANTS: Healthy pregnant women from gestation week 26. RESULTS: Forty-five women were randomised (twenty-two control, twenty-three intervention). Compared with the control group, the intervention group improved diet quality prior to birth (5·66 (95 % CI 1·65, 9·67), Cohen's d: 0·82 (se 0·33)). The intervention improved dietary variety (1·05 (95 % CI 0·17, 1·94), d: 0·66 (se 0·32)) and increased intakes of prebiotic (0·8 (95 % CI 0·27, 1·33), d: 0·91 (se 0·33)) and probiotic foods (1·05 (95 % CI 0·57, 1·53), d: 1·3(se 0·35)) over the whole study period compared with the control group. CONCLUSION: A dietary intervention focused on 'eating for the gut microbiota' can improve aspects of perinatal diet quality during and after pregnancy.

4.
Clin Epigenetics ; 12(1): 158, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092643

RESUMO

BACKGROUND: DNA methylation-based biological age (DNAm age) is an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. However, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan. RESULTS: In order to investigate the genetic and environmental causes of DNAm age variation across the lifespan, we pooled genome-wide DNA methylation data for 4217 people aged 0-92 years from 1871 families. DNAm age was calculated using the Horvath epigenetic clock. We estimated familial correlations in DNAm age for monozygotic (MZ) twin, dizygotic (DZ) twin, sibling, parent-offspring, and spouse pairs by cohabitation status. Genetic and environmental variance components models were fitted and compared. We found that twin pair correlations were - 0.12 to 0.18 around birth, not different from zero (all P > 0.29). For all pairs of relatives, their correlations increased with time spent living together (all P < 0.02) at different rates (MZ > DZ and siblings > parent-offspring; P < 0.001) and decreased with time spent living apart (P = 0.02) at similar rates. These correlation patterns were best explained by cohabitation-dependent shared environmental factors, the effects of which were 1.41 (95% confidence interval [CI] 1.16 to 1.66) times greater for MZ pairs than for DZ and sibling pairs, and the latter were 2.03 (95% CI 1.13 to 9.47) times greater than for parent-offspring pairs. Genetic factors explained 13% (95% CI - 10 to 35%) of variation (P = 0.27). Similar results were found for another two epigenetic clocks, suggesting that our observations are robust to how DNAm age is measured. In addition, results for the other clocks were consistent with there also being a role for prenatal environmental factors in determining their variation. CONCLUSIONS: Variation in DNAm age is mostly caused by environmental factors, including those shared to different extents by relatives while living together and whose effects persist into old age. The equal environment assumption of the classic twin study might not hold for epigenetic aging.

5.
Environ Health Perspect ; 128(9): 97003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32930613

RESUMO

BACKGROUND: Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for in utero cigarette smoke exposure. METHODS: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina's Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression. RESULTS: Sensitivity and specificity values for the best performing previously developed classifier ("Reese Score") were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966. CONCLUSION: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076.

6.
Nutr Metab Cardiovasc Dis ; 30(10): 1609-1621, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32682747

RESUMO

BACKGROUND AND AIMS: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. METHODS AND RESULTS: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (ß = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (ß = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (ß = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. CONCLUSIONS: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças em Gêmeos/etiologia , Doenças Metabólicas/etiologia , Gêmeos , Adiposidade , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Peso ao Nascer , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Colesterol/sangue , Doenças em Gêmeos/sangue , Doenças em Gêmeos/genética , Doenças em Gêmeos/fisiopatologia , Feminino , Idade Gestacional , Nível de Saúde , Humanos , Insulina/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/genética , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Estudos em Gêmeos como Assunto , Adulto Jovem
7.
Sci Rep ; 10(1): 7954, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409670

RESUMO

Humans are host to a multitude of microorganisms that rapidly populate the body at birth, subject to a complex interplay that is dependent on host genetics, lifestyle, and environment. The host-associated microbiome, including the oral microbiome, presents itself in a complex ecosystem important to health and disease. As the most common chronic disease globally, dental caries is induced by host-microbial dysbiosis in children and adults. Multiple biological and environmental factors are likely to impact disease predisposition, onset, progression, and severity, yet longitudinal studies able to capture these influences are missing. To investigate how host genetics and environment influenced the oral microbial communities over time, we profiled supragingival plaque microbiomes of dizygotic and monozygotic twins during 3 visits over 12-months. Dental plaque DNA samples were amplified by targeting the 16S rRNA gene V4 region, and microbial findings were correlated with clinical, diet and genetic metadata. We observed that the oral microbiome variances were shaped primarily by the environment when compared to host genetics. Among the environmental factors shaping microbial changes of our subjects, significant metadata included age of the subject, and the age by which subjects initiated brushing habits, and the types of actions post-brushing. Relevant heritability of the microbiome included Actinomyces and Capnocytophaga in monozygotic twins and Kingella in dizygotic twins. Corynebacterium and Veillonella abundances were associated with age, whereas Aggregatibacter was associated with younger subjects. Streptococcus abundance showed an inverse association over time, and Selenomonas abundances increased with brushing frequency per day. Unraveling the exact biological mechanisms in caries has the potential to reveal novel host-microbial biomarkers, pathways, and targets important to effective preventive measures, and early disease control in children.


Assuntos
Microbiota , Boca/microbiologia , Gêmeos , Envelhecimento , Criança , Feminino , Hábitos , Humanos , Estudos Longitudinais , Masculino , Higiene Bucal
8.
Brain Behav Immun ; 87: 660-665, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32119900

RESUMO

Cardiometabolic disease is a leading cause of adult morbidity and mortality globally. There is considerable evidence that childhood adversity is associated with markers of cardiometabolic disease risk in childhood, including obesity, blood pressure trajectories, and chronic inflammation. Experiences of racial discrimination may be an important, yet under explored, form of childhood adversity influencing childhood cardiometabolic risk. This study aimed to examine associations between self-reported racial discrimination and cardiometabolic risk markers among children. A total of 124 children (73 female) aged 11.4 years (SD 0.71) participated in the study. Most children (n = 79) identified as being from an Indigenous or an ethnic minority background. Markers of cardiometabolic risk were BMI, waist circumference, weight height ratio, systolic and diastolic blood pressure, and five inflammatory markers (C-reactive protein (CRP), Interleukin (IL)-1ß, IL-6, IL-8, and TNF-α). Results showed that two or more reported experiences of racial discrimination were associated with increased BMI z-score (Beta 0.58, 95% CI 0.18, 0.99), waist circumference (Beta 4.91 cm, 95% CI 0.71, 9.1), systolic blood pressure (Beta 2.07 mmHg, 95% CI 0.43, 3.71) and IL-6 (Beta 0.13, 95% CI 0.00, 0.27) and marginally associated with TNF-α (Beta 0.22, 95% CI -0.09, 0.54) after adjusting for socio-demographic covariates. Findings from this study suggest the need to address racism and racial discrimination as important social determinants of cardiometabolic risk and of the inequitable burden of cardiometabolic disease experienced by those from Indigenous and minoritized ethnic backgrounds.

9.
J Cachexia Sarcopenia Muscle ; 11(4): 887-898, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32067420

RESUMO

BACKGROUND: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. METHODS: To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated DNA methylation patterns in skeletal muscle. RESULTS: The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. CONCLUSIONS: We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.

10.
Dev Cogn Neurosci ; 41: 100750, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31999567

RESUMO

Magnetic Resonance Imaging (MRI) in paediatric cohorts is often complicated by reluctance to enter the scanner and head motion-related imaging artefacts. The process is particularly challenging for children with neurodevelopmental disorders where coping with novel task demands in an unfamiliar setting may be more difficult due to symptom-related deficits or distress. These issues often give rise to excessive head motion that can significantly reduce the quality of images acquired, or render data unusable. Here we report an individualised MRI training procedure that enables children with Autism Spectrum Disorders (ASD) to better tolerate the MRI scanner environment based on a child-focused approach and individualised familiarisation strategies, including a pre-visit interview, familiarisation package, and personalised rewards. A medical imaging mobile application was utilised to familiarise participants to multi-sensory aspects of the neuroimaging experience through a variety of themed mini-games and activities. The MRI training procedure was implemented for monozygotic twins (n = 12; 6 twin pairs; age range 7.1-12.9 years) concordant or discordant for ASD. MRI image quality indices were better or comparable to images acquired from a large independent multi-centre ASD cohort. Present findings are promising and suggest that child-focused strategies could improve the quality of paediatric neuroimaging in clinical populations.


Assuntos
Encéfalo/patologia , Imagem por Ressonância Magnética/métodos , Transtornos do Neurodesenvolvimento/fisiopatologia , Neuroimagem/métodos , Transtorno do Espectro Autista/patologia , Criança , Feminino , Humanos , Masculino
11.
Twin Res Hum Genet ; 23(1): 8-15, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31983355

RESUMO

In 1984, Hrubec and Robinette published what was arguably the first review of the role of twins in medical research. The authors acknowledged a growing distinction between two categories of twin studies: those aimed at assessing genetic contributions to disease and those aimed at assessing environmental contributions while controlling for genetic variation. They concluded with a brief section on recently founded twin registries that had begun to provide unprecedented access to twins for medical research. Here we offer an overview of the twin research that, in our estimation, best represents the field has progress since 1984. We start by summarizing what we know about twinning. We then focus on the value of twin study designs to differentiate between genetic and environmental influences on health and on emerging applications of twins in multiple areas of medical research. We finish by describing how twin registries and networks are accelerating twin research worldwide.


Assuntos
Doenças em Gêmeos/genética , Interação Gene-Ambiente , Estudos em Gêmeos como Assunto , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Pesquisa Biomédica/métodos , Doenças em Gêmeos/congênito , Doenças em Gêmeos/embriologia , Epigênese Genética/fisiologia , Feminino , Humanos , Masculino , Microbiota/genética , Sistema de Registros , Células-Tronco/metabolismo , Células-Tronco/patologia
12.
Twin Res Hum Genet ; 22(6): 438-445, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31767048

RESUMO

Twins Research Australia (TRA) is a community of twins and researchers working on health research to benefit everyone, including twins. TRA leads multidisciplinary research through the application of twin and family study designs, with the aim of sustaining long-term twin research that, both now and in the future, gives back to the community. This article summarizes TRA's recent achievements and future directions, including new methodologies addressing causation, linkage to health, economic and educational administrative datasets and to geospatial data to provide insight into health and disease. We also explain how TRA's knowledge translation and exchange activities are key to communicating the impact of twin studies to twins and the wider community. Building researcher capability, providing registry resources and partnering with all key stakeholders, particularly the participants, are important for how TRA is advancing twin research to improve health outcomes for society. TRA provides researchers with open access to its vibrant volunteer membership of twins, higher order multiples (multiples) and families who are willing to consider participation in research. Established four decades ago, this resource facilitates and supports research across multiple stages and a breadth of health domains.


Assuntos
Pesquisa Biomédica , Doenças em Gêmeos/epidemiologia , Sistema de Registros/estatística & dados numéricos , Projetos de Pesquisa/normas , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Austrália/epidemiologia , Doenças em Gêmeos/genética , Doenças em Gêmeos/patologia , Humanos , Incidência , Inquéritos e Questionários
13.
JMIR Res Protoc ; 8(10): e14771, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638593

RESUMO

BACKGROUND: The early life gut microbiota are an important regulator of the biological pathways contributing toward the pathogenesis of noncommunicable disease. It is unclear whether improvements to perinatal diet quality could alter the infant gut microbiota. OBJECTIVE: The aim of this study is to assess the efficacy of a perinatal educational dietary intervention in influencing gut microbiota in mothers and infants 4 weeks after birth. METHODS: The Healthy Parents, Healthy Kids randomized controlled trial aimed to recruit 90 pregnant women from Melbourne, Victoria, Australia. At week 26 of gestation, women were randomized to receive dietary advice from their doctor (n=45), or additionally receive a dietary intervention (n=45). The intervention included an educational workshop and 2 support calls aiming to align participants' diets with the Australian Dietary Guidelines and increase intakes of prebiotic and probiotic foods. The educational design focused on active learning and self-assessment. Behavior change techniques were used to support dietary adherence, and the target behavior was eating for the gut microbiota. Exclusion criteria were age under 18 years, diagnosed mental illnesses, obesity, diabetes mellitus, diagnosed bowel conditions, exclusion diets, illicit drug use, antibiotic use, prebiotic or probiotic supplementation, and those lacking dietary autonomy. The primary outcome measure is a between-group difference in alpha diversity in infant stool collected 4 weeks after birth. Secondary outcomes include evaluating the efficacy of the intervention in influencing infant and maternal stool microbial composition and short chain fatty acid concentrations, epigenetic profile, and markers of inflammation and stress, as well as changes in maternal dietary intake and well-being. The study and intervention feasibility and acceptance will also be evaluated as secondary outcomes. RESULTS: The study results are yet to be written. The first participant was enrolled on July 28, 2016, and the final follow-up assessment was completed on October 11, 2017. CONCLUSIONS: Data from this study will provide new insights regarding the ability of interventions targeting the perinatal diet to alter the maternal and infant gut microbiota. If this intervention is proven, our findings will support larger studies aiming to guide the assembly of gut microbiota in early life. TRIAL REGISTRATION: Australian Clinical Trials Registration Number ACTRN12616000936426; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370939. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14771.

14.
BMJ Open ; 9(10): e029332, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619420

RESUMO

INTRODUCTION: Worldwide, 10%-20% of children and adolescents experience mental health conditions. However, most such disorders remain undiagnosed until adolescence or adulthood. Little is known about the factors that influence mental health in children and adolescents, especially in low and middle-income countries (LMIC), where environmental threats, such as poverty and war, may affect optimal neurodevelopment. Cohort studies provide important information on risks and resilience across the life course by enabling tracking of the effects of early life environment on health during childhood and beyond. Large birth cohort studies, including twin cohorts that can be aetiologically informative, have been conducted within high-income countries but are not generalisable to LMIC. There are limited longitudinal birth cohort studies in LMIC. METHODS: We sought to enhance the volume of impactful research in Sri Lanka by establishing a Centre of Excellence for cohort studies. The aim is to establish a register of infant, child and adolescent twins, including mothers pregnant with twins, starting in the districts of Colombo (Western Province) and Vavuniya (Northern Province). We will gain consent from twins or parents for future research projects. This register will provide the platform to investigate the aetiology of mental illness and the impact of challenges to early brain development on future mental health. Using this register, we will be able to conduct research that will (1) expand existing research capacity on child and adolescent mental health and twin methods; (2) further consolidate existing partnerships and (3) establish new collaborations. The initiative is underpinned by three pillars: high-quality research, ethics, and patient and public involvement and engagement (PPIE). ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Review Committee of Sri Lanka Medical Association and Keele University's Ethical Review Panel. In addition to journal publications, a range of PPIE activities have been conducted.


Assuntos
Países em Desenvolvimento , Transtornos Mentais/etiologia , Sistema de Registros , Gêmeos , Adolescente , Pesquisa Biomédica , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Saúde Mental , Projetos de Pesquisa , Sri Lanka , Estudos em Gêmeos como Assunto , Gêmeos/psicologia
15.
Front Genet ; 10: 770, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616461

RESUMO

Background: Several studies have shown effects of current and maternal smoking during pregnancy on DNA methylation of CpG sites in newborns and later in life. Here, we hypothesized that there are long-term and persistent epigenetic effects following maternal smoking during pregnancy on adolescent offspring DNA methylation, independent of paternal and postnatal smoke exposure. Furthermore, we explored the association between DNA methylation and cardiometabolic risk factors at 17 years of age. Materials and Methods: DNA methylation was measured using the Illumina HumanMethylation450K BeadChip in whole blood from 995 participants attending the 17-year follow-up of the Raine Study. Linear mixed effects models were used to identify differential methylated CpGs, adjusting for parental smoking during pregnancy, and paternal, passive, and adolescent smoke exposure. Additional models examined the association between DNA methylation and paternal, adolescent, and passive smoking over the life course. Offspring CpGs identified were analyzed against cardiometabolic risk factors (blood pressure, triacylglycerols (TG), high-density lipoproteins cholesterol (HDL-C), and body mass index). Results: We identified 23 CpGs (genome-wide p level: 1.06 × 10-7) that were associated with maternal smoking during pregnancy, including associated genes AHRR (cancer development), FTO (obesity), CNTNAP2 (developmental processes), CYP1A1 (detoxification), MYO1G (cell signalling), and FRMD4A (nicotine dependence). A sensitivity analysis showed a dose-dependent relationship between maternal smoking and offspring methylation. These results changed little following adjustment for paternal, passive, or offspring smoking, and there were no CpGs identified that associated with these variables. Two of the 23 identified CpGs [cg00253568 (FTO) and cg00213123 (CYP1A1)] were associated with either TG (male and female), diastolic blood pressure (female only), or HDL-C (male only), after Bonferroni correction. Discussion: This study demonstrates a critical timing of cigarette smoke exposure over the life course for establishing persistent changes in DNA methylation into adolescence in a dose-dependent manner. There were significant associations between offspring CpG methylation and adolescent cardiovascular risk factors, namely, TG, HDL-C, and diastolic blood pressure. Future studies on current smoking habits and DNA methylation should consider the importance of maternal smoking during pregnancy and explore how the persistent DNA methylation effects of in utero smoke exposure increase cardiometabolic risk.

16.
Epilepsy Res ; 156: 106163, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310899

RESUMO

OBJECTIVE: The aetiology of self-limited epilepsy with centro-temporal spikes (SECTS) remains controversial and a strong genetic basis has long been presumed. The discordant monozygotic twin (MZ) model controls for shared genetic and environmental factors, enabling focus on the potential role of the non-shared environment. METHODS: DNA methylation data was acquired from DNA extracted from three discordant MZ twin pairs, from both new born blood spots before epilepsy onset, and blood samples taken after epilepsy onset. An epigenome-wide analysis was performed, using the Illumina Infinium EPIC array. Differentially methylated regions (DMR) were identified using the bumphunter package in R. Comparative analyses were undertaken at the two different time points as well as a combined analysis independent of time. RESULTS: Many of the top DMR-associated genes have previously been described in neurodevelopmental disorders. The LYPD8 gene was associated with a top-ranked DMR both at birth and across the two time points. CONCLUSION: We have demonstrated the novel utility of the longitudinal, discordant MZ twin model, to facilitate a deeper appreciation of the complex neurobiology of SECTS. The genetic architecture of SECTS is complex and is likely to involve an interplay between genes and environment, in part mediated by epigenetics.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Epilepsia/genética , Criança , Meio Ambiente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Gêmeos Monozigóticos/genética
17.
Epigenomics ; 11(8): 951-968, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31166810

RESUMO

Aim: Epilepsy is a common neurological disorder characterized by recurrent seizures. We performed epigenetic analyses between and within 15 monozygotic (MZ) twin pairs discordant for focal or generalized epilepsy. Methods: DNA methylation analysis was performed using Illumina Infinium MethylationEPIC arrays, in blood and buccal samples. Results: Differentially methylated regions between epilepsy types associated with PM20D1 and GFPT2 genes in both tissues. Within MZ discordant twin pairs, differentially methylated regions associated with OTX1 and ARID5B genes for generalized epilepsy and TTC39C and DLX5 genes for focal epilepsy. Conclusion: This is the first epigenome-wide association study, utilizing the discordant MZ co-twin model, to deepen our understanding of the neurobiology of epilepsy.


Assuntos
Epigênese Genética , Epilepsia/genética , Genoma Humano/genética , Gêmeos Monozigóticos/genética , Adulto , Idoso , Estudos de Coortes , Metilação de DNA , Epigenômica , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Epigenetics ; 14(6): 523-535, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30957644

RESUMO

In recent years, the interest in personalised interventions such as medicine, nutrition, and exercise is rapidly rising to maximize health outcomes and ensure the most appropriate treatments. Exercising regularly is recommended for both healthy and diseased populations to improve health. However, there are sex-specific adaptations to exercise that often are not taken into consideration. While endurance exercise training alters the human skeletal muscle epigenome and subsequent gene expression, it is still unknown whether it does so differently in men and women, potentially leading to sex-specific physiological adaptations. Elucidating sex differences in genetics, epigenetics, gene regulation and expression in response to exercise will have great health implications, as it may enable gene targets in future clinical interventions and may better individualised interventions. This review will cover this topic and highlight the recent findings of sex-specific genetic, epigenetic, and gene expression studies, address the gaps in the field, and offer recommendations for future research.


Assuntos
Adaptação Fisiológica , Epigênese Genética , Exercício Físico/fisiologia , Regulação da Expressão Gênica , Músculo Esquelético/fisiologia , Resistência Física/fisiologia , Feminino , Humanos , Masculino , Resistência Física/genética , Fatores Sexuais
19.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31028158

RESUMO

OBJECTIVES: To explore the relative contributions of genetic and environmental influences on dental caries risk and to investigate fetal and developmental risk factors for dental caries. METHODS: We recruited children from 250 twin pregnancies midgestation and collected demographic, health, and phenotypic data at recruitment, 24 and 36 weeks' gestational age, birth and 18 months, and 6 years of age. 25-hydroxyvitamin D was quantified in mothers at 28 weeks' gestation and in infants at birth. Dental caries and enamel defects were measured at six years of age. We compared concordance for the presence of any caries and advanced caries in monozygotic and dizygotic twin pairs. To investigate environmental risk factors for caries, we fitted multiple logistic regression models using generalized estimating equations to adjust for twin correlation. RESULTS: A total of 345 twins underwent dental assessment, with 111 (32.2%) showing signs of any caries and 83 (24.1%) having advanced caries. There was no evidence of higher concordance in monozygotic twins compared with dizygotic twins, with a difference of 0.05 (95% confidence interval -0.14 to 0.25; P = .30) and 0.00 (95% confidence interval -0.26 to 0.26; P = .50) for any caries and advanced caries, respectively, suggesting that environmental factors, rather than genetics, are the predominant determinant of caries risk. After adjusting for potential confounders, lack of community water fluoridation, hypomineralized second primary molars, dichorionic placenta, and maternal obesity were associated with caries. CONCLUSIONS: Environmental rather than genetic factors drive dental caries risk and arise as early as prenatal life.


Assuntos
Cárie Dentária/epidemiologia , Cárie Dentária/genética , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Meio Ambiente , Interação Gene-Ambiente , Criança , Cárie Dentária/sangue , Doenças em Gêmeos/sangue , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/sangue
20.
J Clin Endocrinol Metab ; 104(7): 3012-3024, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30785999

RESUMO

CONTEXT: "Accelerated aging," assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age. DESIGN: DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA; preserved across cell types) and extrinsic (EEAA; dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development. RESULTS: In 995 participants (49.6% female; age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ-inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors. CONCLUSIONS: Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.


Assuntos
Senilidade Prematura/genética , Envelhecimento/genética , Doenças Cardiovasculares/genética , Metilação de DNA , Epigênese Genética/genética , Inflamação/genética , Absorciometria de Fóton , Adiponectina/metabolismo , Adolescente , Envelhecimento/metabolismo , Senilidade Prematura/metabolismo , Algoritmos , Pressão Sanguínea , Composição Corporal , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Quimiocina CXCL10/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-18/metabolismo , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Medição de Risco , Fatores de Risco , Austrália Ocidental/epidemiologia , Adulto Jovem
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