Reproduction, DNA methylation and biological age

Abstract STUDY QUESTION Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age? SUMMARY ANSWER Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age. WHAT IS KNOWN ALREADY A study of 397 young Filipino women (ages 20–22) observed increasing epigenetic age with an increasing number of pregnancies. STUDY DESIGN, SIZE, DURATION We used data from 2356 non-Hispanic white women (ages 35–74) enrolled in the Sister Study cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina’s HumanMethylation450 BeadChip. We estimated association β-values and 95% CIs using linear regression. MAIN RESULTS AND THE ROLE OF CHANCE All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: β = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: β = 0.12, 95% CI = −0.04, 0.27, P = 0.14; Levine: β = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (β = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (β = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7). LIMITATIONS, REASONS FOR CAUTION We relied on retrospective recall to ascertain reproductive history and pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER Not applicable.

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Impact of depression and stress on placental DNA methylation in ethnically diverse pregnant women

Epigenomics ◽

10.2217/epi-2021-0192 ◽

2021 ◽

Author(s):

Markos Tesfaye ◽

Suvo Chatterjee ◽

Xuehuo Zeng ◽

Paule Joseph ◽

Fasil Tekola-Ayele

Keyword(s):

Dna Methylation ◽

Fetal Brain ◽

Ethnically Diverse ◽

Antenatal Depression ◽

Epigenetic Changes ◽

Clinical Trial Registration ◽

False Discovery ◽

Genome Wide ◽

Neuropsychiatric Diseases ◽

Registration Number

Aim: To investigate the association between placental genome-wide methylation at birth and antenatal depression and stress during pregnancy. Methods: We examined the association between placental genome-wide DNA methylation (n = 301) and maternal depression and stress assessed at six gestation periods during pregnancy. Correlation between DNA methylation at the significantly associated CpGs and expression of nearby genes in the placenta was tested. Results: Depression and stress were associated with methylation of 16 CpGs and two CpGs, respectively, at a 5% false discovery rate. Methylation levels at two of the CpGs associated with depression were significantly associated with expression of ADAM23 and CTDP1, genes implicated in neurodevelopment and neuropsychiatric diseases. Conclusion: Placental epigenetic changes linked to antenatal depression suggest potential fetal brain programming. Clinical trial registration number: NCT00912132 (ClinicalTrials.gov)

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Reproductive history and blood cell DNA methylation later in life: the Young Finns Study

Clinical Epigenetics ◽

10.1186/s13148-021-01215-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Emily W. Harville ◽

Pashupati P. Mishra ◽

Mika Kähönen ◽

Emma Raitoharju ◽

Saara Marttila ◽

...

Keyword(s):

Dna Methylation ◽

Reproductive History ◽

Hypertensive Disorders Of Pregnancy ◽

Birth Registry ◽

Hypertensive Disorders ◽

Epigenetic Age ◽

Epigenetic Age Acceleration ◽

Epigenetic Methylation ◽

History Of ◽

Young Finns Study

Abstract Background Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications. Methods Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices. Results Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure. Conclusions Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.

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Alcohol consumption and methylation-based measures of biological age

The Journals of Gerontology Series A ◽

10.1093/gerona/glab149 ◽

2021 ◽

Author(s):

Jacob K Kresovich ◽

Alexandra M Martinez Lopez ◽

Emma L Garval ◽

Zongli Xu ◽

Alexandra J White ◽

...

Keyword(s):

Dna Methylation ◽

Alcohol Consumption ◽

Biological Age ◽

Average Lifetime ◽

Epigenetic Clock ◽

Genome Wide ◽

Epigenetic Age ◽

Epigenetic Age Acceleration ◽

The Mean ◽

Average Consumption

Abstract Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2,316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration. Recent average alcohol consumption was defined as the mean number of drinks consumed per week within the past year; lifetime average consumption was estimated as the mean number of drinks per year drinking. Whole blood genome-wide DNA methylation was measured with HumanMethylation450 BeadChips and used to assess four epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, GrimAgeAccel). Although alcohol consumption showed little association with most age acceleration metrics, both lifetime and recent average consumption measures were positively associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.30 years, 95% CI: 0.11, 0.48, p=0.002; recent, per additional 5 drinks/week: β=0.19 years, 95% CI: 0.01, 0.37, p=0.04). In a mutually adjusted model, only average lifetime alcohol consumption remained associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.27 years, 95% CI: 0.04, 0.50, p=0.02; recent, per 5 additional drinks/week: β=0.05 years, 95% CI: -0.16, 0.26, p=0.64). Although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clock.

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Methylome modifications in monozygotic twins and in depression

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.854 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S30-S30

Author(s):

L. Fañanás ◽

A. Córdova-Palomera

Keyword(s):

Dna Methylation ◽

Monozygotic Twins ◽

Monozygotic Twin ◽

Epidemiological Studies ◽

P38 Map Kinase ◽

Biological Processes ◽

Genome Wide ◽

Glucocorticoid Signaling ◽

Analytical Strategies ◽

Competing Interest

Epigenetics is the study of gene expression changes that are produced by heritable, though potentially reversible, modifications of chromatin structure or DNA methylation. DNA methylation is interesting in epidemiological studies, due to its accessibility and since previous evidence indicates that large inter-individual differences in methylation levels at some loci may correlate with phenotypic plasticity in changing environments.Prior genome-wide methylomic research on depression has suggested that, together with differential DNA methylation changes, affected co-twins of monozygotic twin pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. However, the putative biological roots of this variability remain largely unexplored.This study evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their depressive status. Genome-wide DNA methylation levels were measured in peripheral blood of 34 twins (17 MZ pairs) using Illumina Infinium Human Methylation450 Beadchip. Two analytical strategies were used to identify differentially methylated probes (DMPs) and variably methylated probes (VMPs).The majority of the DMPs were located in genes previously related to neuropsychiatric phenotypes, such as WDR26, a GWAS hit for MDD whose expression levels have been found altered in blood of depressed individuals.VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling.The findings expand on previous research to indicate that both differential and variable methylation may play a role in the etiopathology of depression, and suggest specific genomic loci of potential interest in the epigenetics of depression.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Preimplantation loss of fertilized human ova: estimating the unobservable

Human Reproduction ◽

10.1093/humrep/deaa048 ◽

2020 ◽

Vol 35 (4) ◽

pp. 743-750 ◽

Cited By ~ 1

Author(s):

Allen J Wilcox ◽

Quaker Harmon ◽

Kevin Doody ◽

Don P Wolf ◽

Eli Y Adashi

Keyword(s):

In Vitro Fertilization ◽

Success Rates ◽

Multiple Sources ◽

Vitro Fertilization ◽

Summary Estimate ◽

Environmental Health Sciences ◽

Registration Number ◽

Competing Interest

Abstract STUDY QUESTION What proportion of fertilized human ova are lost before implantation? SUMMARY ANSWER An estimated 40 to 50% of fertilized ova fail to implant. WHAT IS KNOWN ALREADY Preimplantation loss is not detectable with current technology. Published estimates of preimplantation loss range from 10 to 70%. STUDY DESIGN, SIZE, DURATION We combine data from epidemiologic, demographic, laboratory and in vitro fertilization studies to construct an empirical framework for the estimation of preimplantation loss. This framework is summarized in a user-friendly Excel file included in supplement. PARTICIPANTS/MATERIALS, SETTING, METHODS We draw from multiple sources to generate plausible estimates of fecundability, sterility, transient anovulation, intercourse patterns and the proportion of ova fertilized in the presence of sperm. We combine these estimates to generate a summary estimate of preimplantation loss. This estimate can be considered an average for couples in their prime reproductive years. MAIN RESULTS AND THE ROLE OF CHANCE Under a plausible range of assumptions, we estimate that 40 to 50% of fertilized ova fail to implant. LIMITATIONS, REASONS FOR CAUTION A crucial factor in estimating preimplantation loss is the probability that an ovum will be fertilized when exposed to sperm. Human data are available only from in vitro fertilization (IVF), which may not accurately represent events in vivo. We therefore assume a range of in vivo fertilization rates, from 64% (human IVF data) to 90% (mouse data). WIDER IMPLICATIONS OF THE FINDINGS Our estimate of preimplantation loss takes into account the biological processes relevant to fertilization and loss. Using this empirical basis for estimation, we find support for the usual assumption that risk of loss is highest in the earliest days following fertilization. Furthermore, this framework can provide improved estimates as better reproductive data become available. To the extent that our estimates are accurate, more fertilized ova are apparently lost in vitro than in vivo, suggesting that further improvements in IVF success rates may be possible. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Intramural Program of the National Institute of Environmental Health Sciences, NIH. Professor Adashi serves as Co-Chair of the Safety Advisory Board of Ohana Biosciences, Inc. The other authors have no competing interests. TRIAL REGISTRATION NUMBER N/A.

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Age-related DNA methylation changes are sex-specific: a comprehensive assessment

10.1101/2020.01.15.905224 ◽

2020 ◽

Cited By ~ 2

Author(s):

Igor Yusipov ◽

Maria Giulia Bacalini ◽

Alena Kalyakulina ◽

Mikhail Krivonosov ◽

Chiara Pirazzini ◽

...

Keyword(s):

Dna Methylation ◽

Sex Differences ◽

Meta Analysis ◽

Large Fraction ◽

Age Related ◽

Genome Wide ◽

Epigenetic Age ◽

Age Dependent ◽

Males And Females ◽

Methylation Patterns

AbstractIn humans, females live longer than males but experience a worse longevity, as genome-wide autosomal DNA methylation differences between males and females have been reported. So far, few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes shows age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes, and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and in entropy, we showed that the number of probes showing age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.

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