Paediatrics (RCH) - Research Publications
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ItemNo Preview AvailableGestational weight gain is associated with childhood height, weight and BMI in the Peri/Postnatal Epigenetic Twins Study(CAMBRIDGE UNIV PRESS, 2022-12)Multifetal pregnancies are at risk of adverse maternal, neonatal and long-term health outcomes, and gestational weight gain (GWG) is a potentially modifiable risk factor for several of these. However, studies assessing the associations of GWG with long-term health in twins are rare, and studies which do assess these associations in twins often do not account for gestational age. Since longer gestations are likely to lead to larger GWG and lower risk of adverse outcomes, adjusting for gestational age is necessary to better understand the association of GWG with twin health outcomes. We aimed to explore long-term associations of GWG-for-gestational-age with twin anthropometric measures. The Peri/Postnatal Epigenetic Twins Study (PETS) is a prospective cohort study, which recruited women pregnant with twins from 2007 to 2009. Twins were followed-up at 18 months and 6 years of age. GWG-for-gestational-age z-scores were calculated from pre-pregnancy weight and weight at delivery. We fitted regression models to assess associations of GWG with twin weight, height and BMI at birth, 18 months, and 6 years. Of the 250 women in the PETS, 172 had GWG measured throughout pregnancy. Overall, higher GWG-for-gestational-age z-scores were associated with higher birthweight (β: 0.32 z-scores, 95% Confidence Interval (95% CI): 0.19, 0.45), BMI (β: 0.29 z-scores, 95% CI: 0.14, 0.43) and length (β: 0.27 z-scores, 95% CI: 0.09, 0.45). However, these associations were not observed at 18 months or 6 years of age. GWG was associated with twin length, weight and BMI at birth but not during childhood. Further research is needed to determine the long-term effects of GWG on twin health outcomes.
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ItemDifferential network analysis of oral microbiome metatranscriptomes identifies community scale metabolic restructuring in dental caries.(Oxford University Press (OUP), 2022-11)Dental caries is a microbial disease and the most common chronic health condition, affecting nearly 3.5 billion people worldwide. In this study, we used a multiomics approach to characterize the supragingival plaque microbiome of 91 Australian children, generating 658 bacterial and 189 viral metagenome-assembled genomes with transcriptional profiling and gene-expression network analysis. We developed a reproducible pipeline for clustering sample-specific genomes to integrate metagenomics and metatranscriptomics analyses regardless of biosample overlap. We introduce novel feature engineering and compositionally-aware ensemble network frameworks while demonstrating their utility for investigating regime shifts associated with caries dysbiosis. These methods can be applied when differential abundance modeling does not capture statistical enrichments or the results from such analysis are not adequate for providing deeper insight into disease. We identified which organisms and metabolic pathways were central in a coexpression network as well as how these networks were rewired between caries and caries-free phenotypes. Our findings provide evidence of a core bacterial microbiome that was transcriptionally active in the supragingival plaque of all participants regardless of phenotype, but also show highly diagnostic changes in the ways that organisms interact. Specifically, many organisms exhibit high connectedness with central carbon metabolism to Cardiobacterium and this shift serves a bridge between phenotypes. Our evidence supports the hypothesis that caries is a multifactorial ecological disease.
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ItemNeonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2012-08)Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.
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ItemData Resource Profile: Melbourne Children's LifeCourse initiative (LifeCourse)(OXFORD UNIV PRESS, 2022-10-13)
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ItemChanging genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts(SPRINGERNATURE, 2022-10)BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.
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ItemEarly life affects late-life health through determining DNA methylation across the lifespan: A twin study(ELSEVIER, 2022-03)BACKGROUND: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time. METHODS: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history. FINDINGS: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions. INTERPRETATION: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation. FUNDING: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.
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ItemNo Preview AvailableThe CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins(CAMBRIDGE UNIV PRESS, 2019-12)The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
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ItemNo Preview AvailableTwin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project(CAMBRIDGE UNIV PRESS, 2016-04)We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
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ItemNo Preview AvailableAssociations between birth size and later height from infancy through adulthood: An individual based pooled analysis of 28 twin cohorts participating in the CODATwins project(ELSEVIER IRELAND LTD, 2018-05)BACKGROUND: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. AIM: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. METHODS: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. RESULTS: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. CONCLUSION: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight.
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ItemGenome-scale case-control analysis of CD4+T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease(BMC, 2012)BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune rheumatic disease of largely unknown cause. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune disease. However, nothing is currently known about the potential role of aberrant DNA methylation in JIA. As a first step to addressing this knowledge gap, we have profiled DNA methylation in purified CD4+ T cells from JIA subjects and controls. Genomic DNA was isolated from peripheral blood CD4+ T cells from 14 oligoarticular and polyarticular JIA cases with active disease, and healthy age- and sex-matched controls. Genome-scale methylation analysis was carried out using the Illumina Infinium HumanMethylation27 BeadChip. Methylation data at >25,000 CpGs was compared in a case-control study design. RESULTS: Methylation levels were significantly different (FDR adjusted p<0.1) at 145 loci. Removal of four samples exposed to methotrexate had a striking impact on the outcome of the analysis, reducing the number of differentially methylated loci to 11. The methotrexate-naive analysis identified reduced methylation at the gene encoding the pro-inflammatory cytokine IL32, which was subsequently replicated using a second analysis platform and a second set of case-control pairs. CONCLUSIONS: Our data suggests that differential T cell DNA methylation may be a feature of JIA, and that reduced methylation at IL32 is associated with this disease. Further work in larger prospective and longitudinal sample collections is required to confirm these findings, assess whether the identified differences are causal or consequential of disease, and further investigate the epigenetic modifying properties of therapeutic regimens.