Genome-wide average DNA methylation is determined in utero

Background: Investigating the genetic and environmental causes of variation in genome-wide average DNA methylation (GWAM), a global methylation measure from the HumanMethylation450 array, might give a better understanding of genetic and environmental influences on methylation. Methods: We measured GWAM for 2299 individuals aged 0 to 90 years from seven twin and/or family studies. We estimated familial correlations, modelled correlations with cohabitation history and fitted variance components models for GWAM. Results: The correlation in GWAM for twin pairs was ∼0.8 at birth, decreased with age during adolescence and was constant at ∼0.4 throughout adulthood, with no evidence that twin pair correlations differed by zygosity. Non-twin first-degree relatives were correlated, from 0.17 [95% confidence interval (CI): 0.05-0.30] to 0.28 (95% CI: 0.08-0.48), except for middle-aged siblings (0.01, 95% CI: -0.10-0.12), and the correlation increased with time living together and decreased with time living apart. Spouse pairs were correlated in all studies, from 0.23 (95% CI: 0.3-0.43) to 0.31 (95% CI: 0.05-0.52), and the correlation increased with time living together. The variance explained by environmental factors shared by twins alone was 90% (95% CI: 74-95%) at birth, decreased in early life and plateaued at 28% (95% CI: 17-39%) in middle age and beyond. There was a cohabitation-related environmental component of variance. Conclusions: GWAM is determined in utero by prenatal environmental factors, the effects of which persist throughout life. The variation of GWAM is also influenced by environmental factors shared by family members, as well as by individual-specific environmental factors

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Epigenetic discordance in newborn monozygotic and dizygotic twin pairs

© 2012 Dr. Ji-Hoon Eric JooIntroduction: There is strong evidence that the intrauterine environment can program the long-term health outcomes of the developing fetus. Adverse fetal programming is often also accompanied by low birth weight and this can act as a predictor for later health complications (e.g. hypertension). Although substantiated by numerous animal studies and a small number of human studies, the mechanisms underlying this phenomenon (known as “fetal programming”), remain to be elucidated. Interestingly, epigenetic marks are reprogrammed during early development and subject to change more frequently than genetic mutations. Additionally, epigenetic marks are sensitive to a myriad of environmental influences, suggesting that environmentally mediated epigenetic change during early development may underpin the phenomenon of fetal programming. In order to increase our understanding of this potential mechanistic link, the current study measured aspects of intrauterine environment and epigenetic profile in Human Umbilical Vascular Endothelial Cells (HUVECs) collected from healthy twins at birth as a part of the recently established Pre/Post-natal Epigenetic Twins Study (PETS). HUVECs provide an insight into the fetal programming hypothesis because this cell type is an important mediator in both controlling fetal growth and maintaining cardiovascular health. Furthermore, this study utilised a twin design, controlling for genetic influences (monozygotic twins) or major shared environmental factors (dizygotic twins) on epigenetic profile. Epigenetic profile was measured on a genome-scale using a recently developed DNA methylation microarray and gene expression arrays (as a proxy sum of all epigenetic marks). In addition, the H19/IGF2 imprinted region was examined at a high resolution as an example of a genomic region subject to epigenetic control, also implicated in fetal growth. Materials and Methods: Three approaches were employed to measure within-twin-pair epigenetic discordance in this study: 1. Genome-scale gene expression analysis of 10 MZ pairs; 2. Genome-scale DNA methylation analysis of 13 MZ and 11 DZ pairs; and 3. DNA methylation analysis of 33 MZ and 26 DZ pairs on H19/IGF2 imprinted locus. Genome-scale analyses of gene expression and DNA methylation were performed using Illumina BeadChip expression and Infinium methylation microarrays, whilst our H19/IGF2 locus methylation analysis was performed using the Sequenom MassARRAY EpiTYPER platform. Results: Both genome-scale and locus specific analyses identified a range of within-pair epigenetic discordance within MZ twin pairs at birth, indicating epigenetic drift in utero most likely due to subtle differences in the in utero environment together with stochastic factors. However, evidence of a genetic influence on epigenetic profile was also found, as within twin pair discordances were generally lower for MZ twins relative to DZ twins and unrelated individuals. By regressing within-pair discordance for gene expression and DNA methylation with birth weight discordance, we were able to identify a number of genes which may play an important role in fetal growth and which provide a potential mechanism for the fetal programming hypothesis. In addition, we show common involvement of genes which are discordantly expressed (i.e. hypervariable genes) in immune reponse and response to external signals and differently methylated genes in cell death and proliferation. This study also shows a greater variation in DNA methylation in regions distant from CpG islands than the islands themselves, providing compelling evidence in support of the important role of DNA methylation at CpG dinucleotides proximal to CpG islands (CpG island shores and shelves). We also utilised publically available gene expression microarray data of twins of different ages and compared their gene expression discordance with those detected at birth in our twins and found an increasing epigenetic discordance associated with the age. Finally, the data from our concurrent studies of additional tissues (cord blood mononuclear cells, buccal, placental cells) revealed a highly tissue specific DNA methylation pattern in the H19/IGF2 region. Conclusions: The findings of this study have revealed multiple levels of regulation of epigenetic profile occurring in humans prior to birth. It supports a role for the in utero period specifying the epigenetic profile in response to maternal nutrition and other environmental exposures (in addition to other stochastic influences), with implications for the fetus’ immediate, as well as long-term health outcomes

DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome

Mounting evidence from both animal and human studies suggests that the epigenome is in constant drift over the life course in response to stochastic and environmental factors. In humans, this has been highlighted by a small number of studies that have demonstrated discordant DNA methylation patterns in adolescent or adult monozygotic (MZ) twin pairs. However, to date, it remains unclear when such differences emerge, and how prevalent they are across different tissues. To address this, we examined the methylation of four differentially methylated regions associated with the IGF2/H19 locus in multiple birth tissues derived from 91 twin pairs: 56 MZ and 35 dizygotic (DZ). Tissues included cord blood-derived mononuclear cells and granulocytes, human umbilical vein endothelial cells, buccal epithelial cells and placental tissue. Considerable variation in DNA methylation was observed between tissues and between unrelated individuals. Most interestingly, methylation discordance was also present within twin pairs, with DZ pairs showing greater discordance than MZ pairs. These data highlight the variable contribution of both intrauterine environmental exposures and underlying genetic factors to the establishment of the neonatal epigenome of different tissues and confirm the intrauterine period as a sensitive time for the establishment of epigenetic variability in humans. This has implications for the effects of maternal environment on the development of the newborn epigenome and supports an epigenetic mechanism for the previously described phenomenon of \u27fetal programming\u27 of disease risk

Causes of blood methylomic variation for middle-aged women measured by the HumanMethylation450 array

<p>To address the limitations in current classic twin/family research on the genetic and/or environmental causes of human methylomic variation, we measured blood DNA methylation for 479 women (mean age 56 years) including 66 monozygotic (MZ), 66 dizygotic (DZ) twin pairs and 215 sisters of twins, and 11 random technical duplicates using the HumanMethylation450 array. For each methylation site, we estimated the correlation for pairs of duplicates, MZ twins, DZ twins, and siblings, fitted variance component models by assuming the variation is explained by genetic factors, by shared and individual environmental factors, and by independent measurement error, and assessed the best fitting model. We found that the average (standard deviation) correlations for duplicate, MZ, DZ, and sibling pairs were 0.10 (0.35), 0.07 (0.21), -0.01 (0.14) and -0.04 (0.07). At the genome-wide significance level of 10⁻⁷, 93.3% of sites had no familial correlation, and 5.6%, 0.1%, and 0.2% of sites were correlated for MZ, DZ, and sibling pairs. For 86.4%, 6.9%, and 7.1% of sites, the best fitting model included measurement error only, a genetic component, and at least one environmental component. For the 13.6% of sites influenced by genetic and/or environmental factors, the average proportion of variance explained by environmental factors was greater than that explained by genetic factors (0.41 vs. 0.37, <i>P</i> value <10⁻¹⁵). Our results are consistent with, for middle-aged woman, blood methylomic variation measured by the HumanMethylation450 array being largely explained by measurement error, and more influenced by environmental factors than by genetic factors.</p