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1.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity 
Diabetes  2011;60(5):1528-1534.
OBJECTIVE
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
RESEARCH DESIGN AND METHODS
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
RESULTS
In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239).
CONCLUSIONS
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
2.  Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content 
Calcified tissue international  2011;90(2):120-127.
Aim
Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year old children.
Methods
We used Sequenom MassARRAY to assess the methylation status of 2 CpGs in the eNOS promoter, identified from our previous study, in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years (Lunar DPXL DXA instrument).
Results
Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553+, after taking account of age and sex there was a strong positive association between methylation status and the child’s whole body bone area (r=0.28,p=0.02), bone mineral content (r=0.34,p=0.005) and areal bone mineral density (r=0.34,p=0.005) at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass.
Conclusions
Our findings suggest an association between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. This supports a role for eNOS in bone growth and metabolism and implies that its contribution may at least in part occur during early skeletal development.
doi:10.1007/s00223-011-9554-5
PMCID: PMC3629299  PMID: 22159788
Epigenetic; methylation; umbilical cord; eNOS; DXA
3.  Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth 
Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X Receptor-alpha (RXRA) is an essential cofactor in the action of 1,25(OH)2-vitamin D, and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women’s Survey). Relationships between maternal plasma 25(OH)-vitamin D concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, higher % methylation at 4 out of 6 RXRA CpG sites measured was correlated with lower offspring % bone mineral content (%BMC) (β=−0.02 to −0.04%/SD, p=0.002 to 0.043) and BMC corrected for body size (β=−2.1 to −3.4g/SD, p=0.002 to 0.047), with a further site associated with %BMC only. Similar relationships for %BMC were observed in a second independent cohort (n=64). Maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β=−3.3 SD/unit, p=0.03). In addition to the mechanistic insights afforded by associations between maternal free 25(OH)-vitamin D index, RXRA methylation in umbilical cord DNA, and childhood BMC, such epigenetic marks in early life might represent novel biomarkers for adverse bone outcomes in the offspring.
doi:10.1002/jbmr.2056
PMCID: PMC3836689  PMID: 23907847
Epigenetic; methylation; umbilical cord; RXRA; vitamin D; DXA
4.  DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults 
Clinical Epigenetics  2012;4(1):21.
Background
The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity.
DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression.
Results
The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC.
Conclusions
As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.
doi:10.1186/1868-7083-4-21
PMCID: PMC3507742  PMID: 23148549
Childhood; Fetal programming; DNA methylation; Insulin-like growth factor; Raine Study; Head circumference
5.  The chromosome 3q25 genomic region is associated with measures of adiposity in newborns in a multi-ethnic genome-wide association study 
Human Molecular Genetics  2013;22(17):3583-3596.
Newborns characterized as large and small for gestational age are at risk for increased mortality and morbidity during the first year of life as well as for obesity and dysglycemia as children and adults. The intrauterine environment and fetal genes contribute to the fetal size at birth. To define the genetic architecture underlying the newborn size, we performed a genome-wide association study (GWAS) in 4281 newborns in four ethnic groups from the Hyperglycemia and Adverse Pregnancy Outcome Study. We tested for association with newborn anthropometric traits (birth length, head circumference, birth weight, percent fat mass and sum of skinfolds) and newborn metabolic traits (cord glucose and C-peptide) under three models. Model 1 adjusted for field center, ancestry, neonatal gender, gestational age at delivery, parity, maternal age at oral glucose tolerance test (OGTT); Model 2 adjusted for Model 1 covariates, maternal body mass index (BMI) at OGTT, maternal height at OGTT, maternal mean arterial pressure at OGTT, maternal smoking and drinking; Model 3 adjusted for Model 2 covariates, maternal glucose and C-peptide at OGTT. Strong evidence for association was observed with measures of newborn adiposity (sum of skinfolds model 3 Z-score 7.356, P = 1.90×10−13, and to a lesser degree fat mass and birth weight) and a region on Chr3q25.31 mapping between CCNL and LEKR1. These findings were replicated in an independent cohort of 2296 newborns. This region has previously been shown to be associated with birth weight in Europeans. The current study suggests that association of this locus with birth weight is secondary to an effect on fat as opposed to lean body mass.
doi:10.1093/hmg/ddt168
PMCID: PMC3736865  PMID: 23575227
6.  Exploring the Developmental Overnutrition Hypothesis Using Parental–Offspring Associations and FTO as an Instrumental Variable 
PLoS Medicine  2008;5(3):e33.
Background
The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.
Methods and Findings
We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)–determined fat mass measured at 9 to 11 y (4,091 parent–offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was −0.08 (95% CI: −0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).
Conclusions
Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9–11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.
Using parental-offspring associations and theFTO gene as an instrumental variable for maternal adiposity, Debbie Lawlor and colleagues found that greater maternal BMI during offspring development does not appear to have a marked effect on offspring fat mass at age 9-11.
Editors' Summary
Background.
Since the 1970s, the proportion of children and adults who are overweight or obese (people who have an unhealthy amount of body fat) has increased sharply in many countries. In the US, 1 in 3 adults is now obese; in the mid-1970s it was only 1 in 7. Similarly, the proportion of overweight children has risen from 1 in 20 to 1 in 5. An adult is considered to be overweight if their body mass index (BMI)—their weight in kilograms divided by their height in meters squared—is between 25 and 30, and obese if it is more than 30. For children, the healthy BMI depends on their age and gender. Compared to people with a healthy weight (a BMI between 18.5 and 25), overweight or obese individuals have an increased lifetime risk of developing diabetes and other adverse health conditions, sometimes becoming ill while they are still young. People become unhealthily fat when they consume food and drink that contains more energy than they need for their daily activities. It should, therefore, be possible to avoid becoming obese by having a healthy diet and exercising regularly.
Why Was This Study Done?
Some researchers think that “developmental overnutrition” may have caused the recent increase in waistline measurements. In other words, if a mother is overweight during pregnancy, high sugar and fat levels in her body might permanently affect her growing baby's appetite control and metabolism, and so her offspring might be at risk of becoming obese in later life. If this hypothesis is true, each generation will tend to be fatter than the previous one and it will be very hard to halt the obesity epidemic simply by encouraging people to eat less and exercise more. In this study, the researchers have used two approaches to test the developmental overnutrition hypothesis. First, they have asked whether offspring fat mass is more strongly related to maternal BMI than to paternal BMI; it should be if the hypothesis is true. Second, they have asked whether a genetic indicator of maternal fatness—the “A” variant of the FTO gene—is related to offspring fat mass. A statistical association between maternal FTO genotype (genetic make-up) and offspring fat mass would support the developmental nutrition hypothesis.
What Did the Researchers Do and Find?
In 1991–1992, the Avon Longitudinal Study of Parents and Children (ALSPAC) enrolled about 14,000 pregnant women and now examines their offspring at regular intervals. The researchers first used statistical methods to look for associations between the self-reported prepregnancy BMI of the parents of about 4,000 children and the children's fat mass at ages 9–11 years measured using a technique called dual energy X-ray absorptiometry. Both maternal and paternal BMI were positively associated with offspring fat mass (that is, fatter parents had fatter children) but the effect of maternal BMI was greater than the effect of paternal BMI. When the researchers examined maternal FTO genotypes and offspring fat mass (after allowing for the offspring's FTO genotype, which would directly affect their fat mass), there was no statistical evidence to suggest that differences in offspring fat mass were related to the maternal FTO genotype.
What Do These Findings Mean?
Although the findings from first approach provide some support for the development overnutrition hypothesis, the effect of maternal BMI on offspring fat mass is too weak to explain the recent obesity epidemic. Developmental overnutrition could, however, be responsible for the much slower increase in obesity that began a century ago. The findings from the second approach provide no support for the developmental overnutrition hypothesis, although these results have wide error margins and need confirming in a larger study. The researchers also note that the effects of developmental overnutrition on offspring fat mass, although weak at age 9–11, might become more important at later ages. Nevertheless, for now, it seems unlikely that developmental overnutrition has been a major driver of the recent obesity epidemic. Interventions that aim to improve people's diet and to increase their physical activity levels could therefore slow or even halt the epidemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050033.
See a related PLoS Medicine Perspective article
The MedlinePlus encyclopedia has a page on obesity (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of obesity (in English and Spanish)
The UK National Health Service's health Web site (NHS Direct) provides information about obesity
The International Obesity Taskforce provides information about preventing obesity and on childhood obesity
The UK Foods Standards Agency, the United States Department of Agriculture, and Shaping America's Health all provide useful advice about healthy eating for adults and children
The ALSPAC Web site provides information about the Avon Longitudinal Study of Parents and Children and its results so far
doi:10.1371/journal.pmed.0050033
PMCID: PMC2265763  PMID: 18336062
7.  DNA methylation in neonates born to women receiving psychiatric care 
Epigenetics  2012;7(4):409-414.
Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.
doi:10.4161/epi.19551
PMCID: PMC3368823  PMID: 22419064
antidepressants; depressive symptoms; DNA Methylation; HumanMethylation27 BeadChip; Infinium; prenatal exposures
8.  Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome 
BMC Genomics  2014;15:30.
Background
Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet.
Results
Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 μg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response.
Conclusions
In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status.
doi:10.1186/1471-2164-15-30
PMCID: PMC3902427  PMID: 24433282
Bisphenol A; DNA methylation; Environmental epigenomics; MethylPlex
9.  450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy 
Environmental Health Perspectives  2012;120(10):1425-1431.
Background: Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear.
Objective: We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy.
Methods: We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K).
Results: We found differential DNA methylation at epigenome-wide statistical significance (p-value < 1.06 × 10–7) for 26 CpGs mapped to 10 genes. We replicated findings for CpGs in AHRR, CYP1A1, and GFI1 at strict Bonferroni-corrected statistical significance in a U.S. birth cohort. AHRR and CYP1A1 play a key role in the aryl hydrocarbon receptor signaling pathway, which mediates the detoxification of the components of tobacco smoke. GFI1 is involved in diverse developmental processes but has not previously been implicated in responses to tobacco smoke.
Conclusions: We identified a set of genes with methylation changes present at birth in children whose mothers smoked during pregnancy. This is the first study of differential methylation across the genome in relation to maternal smoking during pregnancy using the 450K platform. Our findings implicate epigenetic mechanisms in the pathogenesis of the adverse health outcomes associated with this important in utero exposure.
doi:10.1289/ehp.1205412
PMCID: PMC3491949  PMID: 22851337
epigenetics; epigenome-wide; in utero; maternal smoking; methylation
10.  DNA methylation signatures in cord blood associated with maternal gestational weight gain: results from the ALSPAC cohort 
BMC Research Notes  2014;7:278.
Background
Epigenetic changes could mediate the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with adverse offspring outcomes. However, studies in humans are lacking. Here, we examined the association of maternal pre-pregnancy BMI and GWG in different periods of pregnancy with cytosine-guanine (CpG) dinucleotide site methylation differences in newborn cord blood DNA from 88 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort using the Illumina GoldenGate Panel I. Pyrosequencing was used for validation of the top associated locus and for replication in 170 non-overlapping mother-offspring pairs from the ALSPAC cohort.
Results
After correction for multiple testing greater GWG in early pregnancy (between 0 to 18 weeks of gestation) was associated with increased DNA methylation levels in four CpG sites at MMP7, KCNK4, TRPM5 and NFKB1 genes (difference in methylation >5% per 400 g/week greater GWG) (q values 0.023 -0.065). Pre-pregnancy BMI and GWG in mid- or late pregnancy were not associated with differential DNA methylation at any CpG site. Pyrosequencing showed that greater GWG in early pregnancy was associated with increased DNA methylation levels at the top associated CpG site at MMP7, although association did not reach statistical significance (p = 0.302). Greater GWG in mid- (p = 0.167) and late-pregnancy (p = 0.037) were also associated with increased DNA methylation levels at the MMP7 CpG site. In addition, newborns of mothers who exceeded the IoM-recommended GWG had higher DNA methylation levels at the MMP7 CpG site than those of mothers with IoM-recommended GWG (p = 0.080). We failed to replicate findings.
Conclusions
Greater GWG in early pregnancy was associated with increased methylation at CpG sites at MMP7, KCNK4, TRPM5 and NFKB1 genes in offspring cord blood DNA. The specific association of GWG in early pregnancy with the top associated CpG site at MMP7 was not validated using Pyrosequencing and it did not replicate. However, given the potential functional relevancy of the four identified loci, we advocate further exploration of them in larger studies.
doi:10.1186/1756-0500-7-278
PMCID: PMC4108052  PMID: 24886386
DNA methylation; Epigenetics; Gestational weight gain
11.  Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood 
Context
Maternal diet during pregnancy has been linked to offspring adiposity, but it is unclear whether maternal polyunsaturated fatty acid (PUFA) status during pregnancy affects offspring body composition.
Objective
We investigated the associations between maternal plasma n-3 and n-6 PUFA status at 34 weeks gestation and offspring body composition.
Design and setting
A prospective UK population-based mother-offspring cohort: the Southampton Women’s Survey (SWS).
Participants
12583 non-pregnant women were recruited into the SWS, of which 1987 delivered a baby before 31st December 2003. 293 mother-child pairs had complete measurements of maternal plasma PUFA concentrations in late pregnancy and offspring body composition at ages 4 and 6 years.
Main Outcomes Measured
Offspring body composition by DXA, yielding fat mass(FM), lean mass(LM), percentage fat mass(%FM) and percentage lean mass(%LM).
Results
Maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 years (β=0.14 SD/SD, p=0.01) and 6 years (β=0.11 SD/SD, p=0.04), but there was no association with offspring lean mass at either age (β=0.005 SD/SD, p=0.89 & β=0.008 SD/SD, p=0.81, respectively). Maternal plasma n-3 PUFA concentration displayed no associations with offspring fat mass at 4 years (β=0.057 SD/SD, p=0.34) or 6 years (β=0.069 SD/SD, p=0.21). Maternal plasma n-3 PUFA status positively correlated with offspring lean mass on univariate analysis (4yrs β=0.11, p=0.06; 6yrs β=0.14, p=0.02), however this was confounded by a positive association with offspring height.
Conclusions
This observational study suggests that maternal n-6 PUFA status during pregnancy might influence offspring adiposity in childhood.
doi:10.1210/jc.2012-2482
PMCID: PMC3604685  PMID: 23162098
long chain polyunsaturated fatty acids; adiposity; body composition; fetal programming
12.  Inter-individual variation of dietary fat-induced mesoderm specific transcript in adipose tissue within inbred mice is not caused by altered promoter methylation 
Mesoderm specific transcript (Mest), an imprinted gene associated with fat mass expansion under conditions of positive energy balance, shows highly variable expression (~80-fold) in white adipose tissue (WAT) of C57BL/6J (B6) mice fed an obesogenic diet. Since B6 mice are essentially genetically invariant and Mest is known to be regulated by CpG methylation within its immediate proximal promoter, the large variability in its expression in adipose tissue has the hallmarks of being controlled via an epigenetic mechanism. In this study, bisulfite sequencing and allelic discrimination analyses were performed to determine whether variations in CpG methylation within the Mest promoter were associated with its expression. Results showed no relationship between CpG methylation in the Mest promoter and high versus low expression in either WAT or isolated adipocytes; and, experiments using a single nucleotide polymorphism in the Mest promoter region between B6 and Castaneus mice showed the expected pattern for an imprinted gene with all maternal alleles being methylated. These data suggest that mechanisms independent of the CpG methylation status of the Mest promoter must underlie the control of its expression during adipose tissue expansion.
PMCID: PMC3951159  PMID: 19875931
imprinting; methylation; epigenetics; genetics; obesity; adiposity
13.  Maternal Leptin Predicts Adiposity of the Neonate 
Background
Increased adiposity at birth may identify infants at high risk of developing obesity. Maternal obesity and hyperglycemia in pregnancy are associated with increased neonatal adiposity; however, features of maternal obesity that contribute to increased neonatal adiposity need further study.
Aims
To measure adiposity in neonates of obese and normal-weight women without gestational diabetes to test the hypothesis that obese women have neonates with increased adiposity compared to neonates of normal-weight women.
Methods
Sixty-one pregnant women, with a normal or obese BMI, and their neonates participated in this cross-sectional study at an academic medical center. Neonatal adiposity, expressed as percent body fat (fat mass/body mass), was measured by air displacement plethysmography and cord blood was assayed for biomarkers.
Results
Adiposity in neonates of obese and normal-weight mothers did not differ. Stratifying mothers by leptin level showed that neo nates born to mothers with higher leptin had significantly higher adiposity (13.2 vs. 11.1%, p = 0.035). In the entire cohort, adiposity positively correlated with cord blood leptin (r = 0.48, p < 0.001) and adiponectin (r = 0.27, p = 0.04) levels.
Conclusion
Obesity in normoglycemic pregnant women was not associated with increased neonatal adiposity. High maternal leptin levels identified neonates with increased adiposity.
doi:10.1159/000355387
PMCID: PMC4123455  PMID: 24334975
14.  APOE Genotype and Cardio-Respiratory Fitness Interact to Determine Adiposity in 8-Year-Old Children from the Tasmanian Infant Health Survey 
PLoS ONE  2011;6(11):e26679.
APOE plays a well established role in lipid metabolism. Animal model evidence suggests APOE may also be associated with adiposity, but this has not been thoroughly investigated in humans. We measured adiposity (BMI, truncal fat mass, waist circumference), physical activity (PA), cardiorespiratory fitness and APOE genotype (E2, E3, E4) in 292 8-year-old children from the Tasmanian Infant Health Survey (TIHS), an Australian population-based prospective birth cohort. Our aims were to examine the association of APOE with child adiposity, and to examine the interplay between this association and other measured factors. We found that APOE was associated with child lipid profiles. APOE was also associated with child adiposity measures. The association was E4 allele-specific, with adiposity lower in the E4-containing group (BMI: Mean difference -0.90 kg/m2; 95% confidence intervals (CI) -1.51, -0.28; p = 0.004). The association of APOE4 with lower BMI differed by fitness status (difference in effect p = 0.002), and was more evident among the less fit (mean difference -1.78 kg/m2; 95% CI -2.74, -0.83; p<0.001). Additionally, associations between BMI and lipids were only apparent in those of lower fitness who did not carry APOE4. Similar overall findings were observed when truncal fat mass and waist circumference were used as alternative adiposity measures. APOE4 and cardiorespitatory fitness could interact to influence child adiposity. In studies addressing the genetic determinants of childhood obesity, the context of child fitness should also be taken into account.
doi:10.1371/journal.pone.0026679
PMCID: PMC3206035  PMID: 22069463
15.  Maternal Diet during Pregnancy Induces Gene Expression and DNA Methylation Changes in Fetal Tissues in Sheep 
Studies in rats and mice have established that maternal nutrition induces epigenetic modifications, sometimes permanently, that alter gene expression in the fetus, which in turn leads to phenotypic changes. However, limited data is available on the influence of maternal diet on epigenetic modifications and gene expression in sheep. Therefore, the objectives of this study were to investigate the impact of different maternal dietary energy sources on the expression of imprinted genes in fetuses in sheep. Ewes were naturally bred to a single sire and from days 67 ± 3 of gestation until necropsy (days 130 ± 1), they were fed one of three diets of alfalfa haylage (HY; fiber), corn (CN; starch), or dried corn distiller’s grains (DG; fiber plus protein plus fat). A total of 26 fetuses were removed from the dams and longissimus dorsi, semitendinosus, perirenal adipose depot, and subcutaneous adipose depot tissues were collected for expression and DNA methylation analyses. Expression analysis of nine imprinted genes and three DNA methyltransferase (DNMTs) genes showed significant effects of the different maternal diets on the expression of these genes. The methylation levels of CpG islands of both IGF2R and H19 were higher in HY and DG than CN fetuses in both males and females. This result is consistent with the low amino acid content of the CN diet, a source of methyl group donors, compared to HY and DG diets. Thus, results of this study provide evidence of association between maternal nutrition during pregnancy and transcriptomic and epigenomic alterations of imprinted genes and DNMTs in the fetal tissues.
doi:10.3389/fgene.2013.00049
PMCID: PMC3617393  PMID: 23577020
maternal nutrition; pregnancy; gene expression; DNA methylation
16.  THE RELATIONSHIP BETWEEN MATERNAL ADIPOSITY AND INFANT WEIGHT GAIN AND CHILDHOOD WHEEZE AND ATOPY 
Thorax  2013;68(4):372-379.
Background
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Methods
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Results
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Discussion
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
doi:10.1136/thoraxjnl-2012-202556
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
17.  Serum Activin A and Follistatin Levels in Gestational Diabetes and the Association of the Activin A-Follistatin System with Anthropometric Parameters in Offspring 
PLoS ONE  2014;9(4):e92175.
Context
The Activin A-Follistatin system has emerged as an important regulator of lipid and glucose metabolism with possible repercussions on fetal growth.
Objective
To analyze circulating activin A, follistatin and follistatin-like-3 (FSTL3) levels and their relationship with glucose metabolism in pregnant women and their influence on fetal growth and neonatal adiposity.
Design and methods
A prospective cohort was studied comprising 207 pregnant women, 129 with normal glucose tolerance (NGT) and 78 with gestational diabetes mellitus (GDM) and their offspring. Activin A, follistatin and FSTL3 levels were measured in maternal serum collected in the early third trimester of pregnancy. Serial fetal ultrasounds were performed during the third trimester to evaluate fetal growth. Neonatal anthropometry was measured to assess neonatal adiposity.
Results
Serum follistatin levels were significantly lower in GDM than in NGT pregnant women (8.21±2.32 ng/mL vs 9.22±3.41, P = 0.012) whereas serum FSTL3 and activin A levels were comparable between the two groups. Serum follistatin concentrations were negatively correlated with HOMA-IR and positively with ultrasound growth parameters such as fractional thigh volume estimation in the middle of the third trimester and percent fat mass at birth. Also, in the stepwise multiple linear regression analysis serum follistatin levels were negatively associated with HOMA-IR (β = −0.199, P = 0.008) and the diagnosis of gestational diabetes (β = −0.138, P = 0.049). Likewise, fractional thigh volume estimation in the middle of third trimester and percent fat mass at birth were positively determined by serum follistatin levels (β = 0.214, P = 0.005 and β = 0.231, P = 0.002, respectively).
Conclusions
Circulating follistatin levels are reduced in GDM compared with NGT pregnant women and they are positively associated with fetal growth and neonatal adiposity. These data suggest a role of the Activin-Follistatin system in maternal and fetal metabolism during pregnancy.
doi:10.1371/journal.pone.0092175
PMCID: PMC3998926  PMID: 24763182
18.  The chromosome 3q25 locus associated with fetal adiposity is not associated with childhood adiposity 
Nutrition & Diabetes  2014;4(9):e138-.
Increased newborn adiposity is associated with later adverse metabolic outcomes. Previous genome-wide association studies (GWAS) demonstrated strong association of a locus on chromosome 3 (3q25.31) with newborn sum of skinfolds, a measure of overall adiposity. Whether this locus is associated with childhood adiposity is unknown. Genotype and sum of skinfolds data were available for 293 children at birth and age 2, and for 350 children at birth and age 6 from a European cohort (Belfast, UK) who participated in the Hyperglycemia and Adverse Pregnancy Outcome GWAS. We examined single nucleotide polymorphisms (SNPs) at the 3q25.31 locus associated with newborn adiposity. Linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed. In both cohorts, a positive association was observed between all SNPs and sum of skinfolds at birth (P=2.3 × 10−4, β=0.026 and P=4.8 × 10−4, β=0.025). At the age of 2 years, a non-significant negative association was observed with sum of skinfolds (P=0.06; β =−0.015). At the age of 6 years, there was no evidence of association (P=0.86; β=0.002). The 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion.
doi:10.1038/nutd.2014.35
PMCID: PMC4183976  PMID: 25244357
19.  Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys 
Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (r S-values>−0.62), but in girls only 207 (41%) showed inverse correlation (r S-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.
doi:10.1017/S2040174414000221
PMCID: PMC4283288  PMID: 24965135
450 K; cancer; CpG; development; epigenetic; fetal
20.  Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(3):e1001618.
Here, Timpson and colleagues performed a Mendelian Randomization analysis to determine whether childhood adiposity causally influences levels of physical activity. The results suggest that increased adiposity causes a reduction in physical activity in children; however, this study does not exclude lower physical activity also leading to increasing adiposity.
Please see later in the article for the Editors' Summary
Background
Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose–response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.
Methods and Findings
The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity.
In observational analysis, a 3.3 kg/m2 (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10−16), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10−29), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10−4). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.
Conclusions
Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed.
Why Was This Study Done?
One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e., obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children.
What Did the Researchers Do and Find?
The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain.
What Do These Findings Mean?
This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of “reverse causation,” i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity. This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618.
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups
The International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesity
MedlinePlus—which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations—has a page on obesity
Additional information on the Avon Longitudinal Study of Parents and Children is available
The British Medical Journal has an article that describes Mendelian randomization
doi:10.1371/journal.pmed.1001618
PMCID: PMC3958348  PMID: 24642734
21.  Maternal Methyl Donors Supplementation during Lactation Prevents the Hyperhomocysteinemia Induced by a High-Fat-Sucrose Intake by Dams 
Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle.
doi:10.3390/ijms141224422
PMCID: PMC3876120  PMID: 24351826
cardiovascular; HFS diet; homocysteine; maternal programming; methyl donors; obesity
22.  Maternal size in pregnancy and body composition in children 
Context:
Evidence suggests that babies' fat mass at birth is greater if their mothers were themselves fatter during pregnancy, but it is unclear whether this association persists into childhood.
Objective:
To examine the relation between maternal size in pregnancy, early growth and body composition in children.
Design:
Prospective cohort study
Setting:
Southampton, UK.
Participants:
216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy.
Main outcome measures:
Fat mass and lean mass measured by dual-energy X-ray absorptiometry, adjusted for height (“fat mass index” and “lean mass index”).
Results:
Fat mass index at age nine years was greater in children whose mothers had a larger mid-upper arm circumference in late pregnancy or a higher pre-pregnant body mass index. For one standard deviation (SD) increase in maternal mid-upper arm circumference in late pregnancy, fat mass index rose by 0.26 (95% CI 0.06-0.46) SD in boys and by 0.44 (95% CI 0.31-0.57) SD in girls. For one SD increase in maternal pre-pregnant BMI, fat mass index rose by 0.26 (95% CI 0.04-0.48) SD in boys and by 0.42 (95% CI 0.29-0.56) SD in girls.
Conclusions:
Mothers with a higher pre-pregnant body mass index or a larger mid-upper arm circumference during pregnancy tend to have children with greater adiposity at age nine. The extent to which this is attributable to genetic factors, the influence of maternal lifestyle on that of her child, or maternal adiposity acting specifically during pregnancy on the child's fat mass cannot be determined in this study.
doi:10.1210/jc.2007-0088
PMCID: PMC2066182  PMID: 17684051
child; body composition; pregnancy; birth weight; weight gain; infancy
23.  Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins 
Epigenetics  2013;8(10):1069-1079.
Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non-shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p < 0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease.
doi:10.4161/epi.25908
PMCID: PMC3891688  PMID: 23917818
DNA methylation; imprinted genes; maternal factors; twins; developmental origins of health and disease (DOHaD)
24.  Passive and active DNA methylation and the interplay with genetic variation in gene regulation 
eLife  2013;2:e00523.
DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression.
DOI: http://dx.doi.org/10.7554/eLife.00523.001
eLife digest
Variations occur throughout our genome. These variations can cause genes to be expressed (switched on) in slightly different ways among individuals. Moreover, the same gene can also be expressed in different ways in different cells within an individual. A third level of variation is supplied by epigenetic markers: these are molecules that bind to the DNA at specific points and can have profound effects on the expression of nearby genes. One such epigenetic marker is the addition of a methyl group to a cytosine base, a process that is known as DNA methylation.
DNA methylation usually happens when a cytosine base is next to a guanine base, forming a CpG site. In mammals, most CpG sites have methyl groups attached, although regions with a lot of CpG sites (called CpG islands) are mostly unmethylated. Initial studies suggested that methylation prevented particular genes from being expressed, but more recent work has indicated that methylation can be associated with both reduced and increased expression of genes. Moreover, it is not clear if this association is active (i.e., changes in methylation drive changes in gene expression) or passive (DNA methylation is the result of gene regulation).
Now, Gutierrez-Arcelus et al. have carried out a large-scale study to clarify the relationships between three different types of gene-related variations among individuals. They extracted fibroblasts, T-cells and lymphoblastoid cells from the umbilical cords of 204 babies, and analysed them for variations in DNA sequence, gene expression and DNA methylation. Their results show that the associations between the three are more complex than was previously thought.
Gutierrez-Arcelus et al. show that the mechanisms that control the association between the variations in DNA methylation and gene expression in individuals are likely to be different to those that are responsible for the establishment of methylation patterns during the process of cell differentiation. They also find that the association between DNA methylation and gene expression can be either active or passive, and can depend on the context in which they occur in our genome. Finally, where the two copies or alleles of a gene are not equally expressed in a given cell, the difference in expression is primarily regulated by DNA sequence variation, with DNA methylation having little or no role on its own. Equally complex interactions and effects are expected in further studies of genetic and epigenetic variation.
DOI: http://dx.doi.org/10.7554/eLife.00523.002
doi:10.7554/eLife.00523
PMCID: PMC3673336  PMID: 23755361
methylation; gene regulation; epigenetics; genome variation; Human
25.  Array-based Profiling of DNA Methylation Changes Associated with Alcohol Dependence 
Background
Epigenetic regulation through DNA methylation may influence vulnerability to numerous disorders, including alcohol dependence (AD).
Methods
Peripheral blood DNA methylation levels of 384 CpGs in the promoter regions of 82 candidate genes were examined in 285 African Americans (AAs; 141 AD cases and 144 controls) and 249 European Americans (EAs; 144 AD cases and 105 controls) using Illumina GoldenGate Methylation Array assays. Association of AD and DNA methylation changes were analyzed using multivariate analyses of covariance with frequency of intoxication, sex, age and ancestry proportion as covariates. CpGs showing significant methylation alterations in AD cases were further examined in a replication sample (49 EA cases and 32 EA controls) using Sequenom’s MassARRAY EpiTYPER technology.
Results
In AAs, two CpGs in two genes (GABRB3 and POMC) were hypermethylated in AD cases compared to controls (P≤0.001). In EAs, six CpGs in six genes (HTR3A, NCAM1, DRD4, MBD3, HTR2B and GRIN1) were hypermethylated in AD cases compared to controls (P≤0.001); CpG cg08989585 in the HTR3A promoter region showed a significantly higher methylation level in EA cases than in EA controls after Bonferroni correction (P=0.00007). Additionally, methylation levels of six CpGs (including cg08989585) in the HTR3A promoter region were analyzed in the replication sample. Although the six HTR3A promoter CpGs did not show significant methylation differences between EA cases and EA controls (P=0.067–0.877), the methylation level of CpG cg08989585 was non-significantly higher in EA cases (26.9%) than in EA controls (18.6%) (P=0.139).
Conclusions
The findings from this study suggest that DNA methylation profile appears to be associated with AD in a population-specific way and the predisposition to AD may result from a complex interplay of genetic variation and epigenetic modifications.
doi:10.1111/j.1530-0277.2012.01928.x
PMCID: PMC3511647  PMID: 22924764
Illumna GoldenGate Methylation Array; Sequenom MassARRAY EpiTYPER; Promoter CpGs; Alcohol Dependence; Peripheral Blood DNA

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