Birth weight associations with psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

AbstractBackgroundThe Developmental Origins of Adult Disease (DOAD) theory predicts that prenatal and early life events shape adult health outcomes. Birth weight is a useful indicator of the foetal experience, and has been associated with multiple adult health outcomes. DNA methylation (DNAm) is one plausible mechanism behind the relationship of birth weight to adult health.MethodsThe Generation Scotland study allows data linkage to historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division. Data linkage with these sources yielded a sample of 4, 710 individuals. Health measures were related to birth weight in regression models. An epigenome-wide association study (EWAS) was performed in a subgroup (n=1, 395), relating adult DNAm from whole blood to birth weight, with replication in an independent sample (n=362). Associations between birth weight and epigenetic clocks were also assessed.FindingsHigher birth weight was significantly associated with reduced incidence of depression and osteoarthritis, higher body mass index, and higher general intelligence (absolute standardised effect size range 0·04 to 0·30, p(FDR)<0·05). Meta-analysis of discovery and replication EWAS studies yielded one genome-wide significant CpG site (p=5·97×10−9), cg00966482. Significant associations between birth weight and Grim Age (p=0·0014) and DNAm-derived telomere length (p=3·3×10−4) are also described.InterpretationOur results demonstrate associations between birth weight and adult health outcomes, with particularly striking effects for depression risk. It also provides support for an association between birth weight and DNAm, describing the first significant EWAS site associated with birth weight in an adult sample.FundingWellcome Trust Strategic Award 104036/Z/14/ZResearch in ContextEvidence before this studyThe associations between birth weight and various adult health outcomes have been well established. DNA methylation is a plausible mechanism through which early life experiences may continue to affect health throughout the lifecourse; however, evidence for birth weight associations with DNA methylation in adulthood has not yet been robustly established. This is likely due to small sample sizes of previous samples, as well as the use of poor-quality birth weight data, such as binary ‘low/normal’ variables or retrospective self-report. Alternatively, work has attempted to describe the persistence into adulthood of DNA methylation at sites identified at birth.Added value of this studyWe investigated genome-wide differential DNA methylation patterns from whole blood using data linkage-derived, continuous birth weight data, in the largest reported adult sample (n=1, 395) with replication (n=362) and meta-analysis. Meta-analysis revealed one epigenome-wide significant CpG site, to our knowledge the first significant EWAS result reported for birth weight in a an adult sample. In addition, we found associations between birth weight and GrimAge and a DNA methylation-derived measure of telomere length, demonstrating accelerated biological ageing in lower birth weight individuals. Together, these results suggest differential methylation exists in adulthood related to birth weight, and this may be relevant to health and mortality.Implications of all the available evidenceAlthough CpG sites differentially methylated with birth weight at parturition may not remain so throughout life, the adult epigenome may still provide information on the impact of birth weight on health outcomes. The adult epigenome, therefore, may represent a useful archive of the foetal experience which results in birth weight variability, and this information may provide clinically useful information in mid-life.

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DNA methylation associated with postpartum depressive symptoms overlaps findings from a genome-wide association meta-analysis of depression

Clinical Epigenetics ◽

10.1186/s13148-019-0769-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Dana M. Lapato ◽

Roxann Roberson-Nay ◽

Robert M. Kirkpatrick ◽

Bradley T. Webb ◽

Timothy P. York ◽

...

Keyword(s):

Dna Methylation ◽

Depressive Symptoms ◽

Health Outcomes ◽

Meta Analysis ◽

Previous History ◽

Depression Scale ◽

Postpartum Depressive Symptoms ◽

Genome Wide ◽

A Genome ◽

Genomic Regions

Abstract Background Perinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology. Results Genome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within 7 months of delivery. Linear models were constructed to identify differentially methylated sites and regions, and permutation testing was utilized to assess significance. Differentially methylated regions (DMRs) were defined as genomic regions of consistent DNAm change with at least two probes within 1 kb of each other. Maternal age, current smoking status, estimated cell-type proportions, ancestry-relevant principal components, days since delivery, and chip position served as covariates to adjust for technical and biological factors. Current postpartum depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Ninety-eight DMRs were significant (false discovery rate < 5%) and overlapped 92 genes. Three of the regions overlap loci from the latest Psychiatric Genomics Consortium meta-analysis of depression. Conclusions Many of the genes identified in this analysis corroborate previous allelic, transcriptomic, and DNAm association results related to depressive phenotypes. Future work should integrate data from multi-omic platforms to understand the functional relevance of these DMRs and refine DNAm association results by limiting phenotypic heterogeneity and clarifying if DNAm differences relate to the timing of onset, severity, duration of perinatal mental health outcomes of the current pregnancy or to previous history of depressive psychopathology.

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DNA Methylation Associated with Postpartum Depressive Symptoms Overlaps Findings from a Genome-wide Association Meta-Analysis of Depression

10.1101/600742 ◽

2019 ◽

Author(s):

Dana M. Lapato ◽

Roxann Roberson-Nay ◽

Robert M. Kirkpatrick ◽

Bradley T. Webb ◽

Timothy P. York ◽

...

Keyword(s):

Dna Methylation ◽

Depressive Symptoms ◽

Health Outcomes ◽

Meta Analysis ◽

Previous History ◽

Depression Scale ◽

Postpartum Depressive Symptoms ◽

Genome Wide ◽

A Genome ◽

Genomic Regions

AbstractBackgroundPerinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology.ResultsGenome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within seven months of delivery. Linear models were constructed to identify differentially methylated sites and regions, and permutation testing was utilized to assess significance. Differentially methylated regions (DMRs) were defined as genomic regions of consistent DNAm change with at least two probes within 1kb of each other. Maternal age, current smoking status, estimated cell-type proportions, ancestry-relevant principal components, days since delivery, and chip position served as covariates to adjust for technical and biological factors. Current postpartum depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Ninety-eight DMRs were significant (False Discovery Rate < 5%) and overlapped 92 genes. Synaptic signaling, neural development, and platelet formation were the most represented biological processes in gene set analysis, and comparison to the 44 loci discovered in the latest Psychiatric Genomics Consortium meta-analysis of depression revealed 3 overlapping regions and significant enrichment (p<0.03).ConclusionsMany of the genes identified in this analysis corroborate previous allelic, transcriptomic, and DNAm association results related to depressive phenotypes. Future work should integrate data from multi-omic platforms to understand the functional relevance of these DMRs and refine DNAm association results by limiting phenotypic heterogeneity and clarifying if DNAm differences relate to the timing of onset, severity, duration of perinatal mental health outcomes of the current pregnancy or to previous history of depressive psychopathology.

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A meta-analysis of neonatal health outcomes from oocyte donation

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174415007898 ◽

2015 ◽

Vol 7 (3) ◽

pp. 257-272 ◽

Cited By ~ 11

Author(s):

D. H. Adams ◽

R. A. Clark ◽

M. J. Davies ◽

S. de Lacey

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Health Outcomes ◽

Very Low Birth Weight ◽

Meta Analysis ◽

Oocyte Donation ◽

Donor Oocyte ◽

Cochrane Reviews ◽

Increased Risk ◽

Weight Outcomes

Donated oocytes are a treatment modality for female infertility which is also associated with increased risks of preeclampsia. Subsequently it is important to evaluate if there is concomitant increased risks for adverse neonatal events in donated oocyte neonates. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the perinatal health outcomes of offspring conceived from donor oocytes compared with autologous oocytes. Meta-analysis was performed on comparable outcomes data. Twenty-eight studies were eligible and included in the review, and of these, 23 were included in a meta-analysis. Donor oocyte neonates are at increased risk of being born with low birth weight (<2500 g) [risk ratio (RR): 1.18, 95% confidence interval (CI): 1.14–1.22, P-value (P)<0.00001], very low birth weight (<1500 g) (RR: 1.24, CI: 1.15–1.35, P<0.00001), preterm (<37 weeks) (RR: 1.26, CI: 1.23–1.30, P<0.00001), of lower gestational age (mean difference −0.3 weeks, CI: −0.35 weeks to −0.25 weeks, P<0.00001), and preterm with low birth weight (RR: 1.24, CI: 1.19–1.29, P<0.00001), when compared with autologous oocyte neonates. Conversely, low birth weight outcomes were improved in term donor oocyte neonates (RR: 0.86, CI: 0.8–0.93, P=0.0003). These negative outcomes remained significant when controlling for multiple deliveries. The donor oocyte risk rates are higher than those found in general ART outcomes, are important considerations for the counselling of infertile patients and may also influence the long term health of the offspring.

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DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2016.02.019 ◽

2016 ◽

Vol 98 (4) ◽

pp. 680-696 ◽

Cited By ~ 395

Author(s):

Bonnie R. Joubert ◽

Janine F. Felix ◽

Paul Yousefi ◽

Kelly M. Bakulski ◽

Allan C. Just ◽

...

Keyword(s):

Dna Methylation ◽

Maternal Smoking ◽

Meta Analysis ◽

Smoking In Pregnancy ◽

Genome Wide ◽

In Pregnancy

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Meta-Analysis of Genome-Wide Association Studies Identifies Novel Functional CpG-SNPs Associated with Bone Mineral Density at Lumbar Spine

International Journal of Genomics ◽

10.1155/2018/6407257 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Chuan Qiu ◽

Hui Shen ◽

Xiaoying Fu ◽

Chao Xu ◽

Hongwen Deng

Keyword(s):

Bone Mineral Density ◽

Dna Methylation ◽

Lumbar Spine ◽

Bone Mineral ◽

Meta Analysis ◽

Mineral Density ◽

Significance Level ◽

Genome Wide ◽

A Genome ◽

Genome Wide Significance

Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n=5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p<7.86×10−7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p<5.00×10−5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel associations that were missed by traditional GWAS. Interestingly, several genomic regions, such as NEK3 and LRP5 regions, contained multiple significant/suggestive CpG-SNPs for lumbar spine BMD, suggesting that multiple neighboring CpG-SNPs may synergistically mediate the DNA methylation level and gene expression pattern of target genes. Furthermore, functional annotation analyses suggested a strong regulatory potential of the identified BMD-associated CpG-SNPs and a significant enrichment in biological processes associated with protein localization and protein signal transduction. Our results provided novel insights into the genetic basis of BMD variation and highlighted the close connections between genetic and epigenetic mechanisms of complex disease.

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Paternal body mass index and offspring DNA methylation: findings from the PACE consortium

10.1101/2020.03.10.20020099 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gemma C Sharp ◽

Rossella Alfano ◽

Akram Ghantous ◽

Jose Urquiza ◽

Sheryl L Rifas-Shiman ◽

...

Keyword(s):

Body Mass Index ◽

Dna Methylation ◽

Health Outcomes ◽

Candidate Gene ◽

Body Mass ◽

Association Studies ◽

Meta Analysis ◽

450K Array ◽

Total N ◽

Candidate Gene Studies

AbstractBackgroundAccumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.Methods and findingsIn the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.ConclusionOur findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions.Author SummaryPrevious small, mostly candidate gene studies have shown associations between paternal pre-pregnancy BMI and offspring blood DNA methylation. However, in our large meta-analysis of co-ordinated EWAS results from a total of 19 datasets across two timepoints, we found little evidence to support these findings, even at imprinted regions. This does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms, or in populations with greater extremes of paternal BMI. More research is warranted to help understand the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.

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Photoperiodic stress induces genotype-specific shift in DNA methylation in Tartary buckwheat

Biologia Futura ◽

10.1556/019.70.2019.31 ◽

2019 ◽

Vol 70 (4) ◽

pp. 278-285

Author(s):

Muhammad Saad ◽

Helen Mary ◽

Umar Amjid ◽

Ghulam Shabir ◽

Kashif Aslam ◽

...

Keyword(s):

Dna Methylation ◽

Flowering Time ◽

Specific Pattern ◽

Plant Response ◽

Tartary Buckwheat ◽

Genome Wide ◽

Total Dna ◽

First Time ◽

Weight Data ◽

Methylation Ratio

Tartary buckwheat, known for its rich source of health beneficial secondary metabolites, is cultivated in many areas of the world. Among different environmental factors, photoperiod strongly influence its growth, flowering time, and ultimately the yield. In this context, epigenetics could contribute significantly in the regulation of plant response against changing environment. Therefore, with the aim to study the involvement of DNA methylation in photoperiod mediated plant response, genome-wide DNA methylation analysis was performed in two accessions (A1 and A2) of Tartary buckwheat using three photoperiodic treatments, i.e., 10-hr light/day (T1), 12-hr light/day (T2), and 14-hr light/day (T3). Flowering time and plant fresh weight data revealed that accessions A1 and A2 prefer T1 and T2 treatments, respectively. Total DNA methylation ratio increased with the increase in photoperiod in accession A1 but decreased under same conditions in accession A2. Full methylation increased significantly while intensive decrease in hemimethylation was noted from T2 to T3 in A1, whereas full methylation strongly increased and hemimethylation strongly decreased from T1 to T2 in A2. Overall, the DNA methylation events appeared more frequently than demethylation events. This study reports for the first time an accession-/genotype specific pattern of shift in the DNA methylation under different photoperiodic treatments that will pave the way toward identification of specific genes involved in the regulation of plant response against photoperiodic stress.

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450K genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal tobacco smoking: implications for birth weight

ISEE Conference Abstracts ◽

10.1289/isee.2016.3548 ◽

2016 ◽

Vol 2016 (1) ◽

Author(s):

Eva Morales* ◽

Nadia Vilahur ◽

Lucas A Salas ◽

Valeria Motta ◽

Mariana F Fernandez ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Tobacco Smoking ◽

Human Placenta ◽

Genome Wide

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DNA Methylation Changes in the IGF1R Gene in Birth Weight Discordant Adult Monozygotic Twins

Twin Research and Human Genetics ◽

10.1017/thg.2015.76 ◽

2015 ◽

Vol 18 (6) ◽

pp. 635-646 ◽

Cited By ~ 17

Author(s):

Pei-Chien Tsai ◽

Jenny Van Dongen ◽

Qihua Tan ◽

Gonneke Willemsen ◽

Lene Christiansen ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Random Effects ◽

Meta Analysis ◽

Monozygotic Twins ◽

Positive Association ◽

Later Life ◽

Significant Positive Association ◽

Association Analyses ◽

A Genome

Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to pre-disposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10−8), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.

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DNA methylation in infants with low and high body fatness

BMC Genomics ◽

10.1186/s12864-020-07169-7 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Pontus Henriksson ◽

Antonio Lentini ◽

Signe Altmäe ◽

David Brodin ◽

Patrick Müller ◽

...

Keyword(s):

Dna Methylation ◽

Body Composition ◽

Birth Weight ◽

Health Outcomes ◽

Fat Mass ◽

Later Life ◽

Fat Free Mass ◽

Buccal Cells ◽

Body Fatness ◽

High Body

Abstract Background Birth weight is determined by the interplay between infant genetics and the intrauterine environment and is associated with several health outcomes in later life. Many studies have reported an association between birth weight and DNA methylation in infants and suggest that altered epigenetics may underlie birthweight-associated health outcomes. However, birth weight is a relatively nonspecific measure of fetal growth and consists of fat mass and fat-free mass which may have different effects on health outcomes which motivates studies of infant body composition and DNA methylation. Here, we combined genome-wide DNA methylation profiling of buccal cells from 47 full-term one-week old infants with accurate measurements of infant fat mass and fat-free mass using air-displacement plethysmography. Results No significant association was found between DNA methylation in infant buccal cells and infant body composition. Moreover, no association between infant DNA methylation and parental body composition or indicators of maternal glucose metabolism were found. Conclusions Despite accurate measures of body composition, we did not identify any associations between infant body fatness and DNA methylation. These results are consistent with recent studies that generally have identified only weak associations between DNA methylation and birthweight. Although our results should be confirmed by additional larger studies, our findings may suggest that differences in DNA methylation between individuals with low and high body fatness may be established later in childhood.

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