Browsing by Author "Maguire, Rachel L"

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    ItemOpen Access
    Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.
    (Clinical epigenetics, 2023-09) Kadalayil, Latha; Alam, Md Zahangir; White, Cory Haley; Ghantous, Akram; Walton, Esther; Gruzieva, Olena; Merid, Simon Kebede; Kumar, Ashish; Roy, Ritu P; Solomon, Olivia; Huen, Karen; Eskenazi, Brenda; Rzehak, Peter; Grote, Veit; Langhendries, Jean-Paul; Verduci, Elvira; Ferre, Natalia; Gruszfeld, Darek; Gao, Lu; Guan, Weihua; Zeng, Xuehuo; Schisterman, Enrique F; Dou, John F; Bakulski, Kelly M; Feinberg, Jason I; Soomro, Munawar Hussain; Pesce, Giancarlo; Baiz, Nour; Isaevska, Elena; Plusquin, Michelle; Vafeiadi, Marina; Roumeliotaki, Theano; Langie, Sabine AS; Standaert, Arnout; Allard, Catherine; Perron, Patrice; Bouchard, Luigi; van Meel, Evelien R; Felix, Janine F; Jaddoe, Vincent WV; Yousefi, Paul D; Ramlau-Hansen, Cecilia H; Relton, Caroline L; Tobi, Elmar W; Starling, Anne P; Yang, Ivana V; Llambrich, Maria; Santorelli, Gillian; Lepeule, Johanna; Salas, Lucas A; Bustamante, Mariona; Ewart, Susan L; Zhang, Hongmei; Karmaus, Wilfried; Röder, Stefan; Zenclussen, Ana Claudia; Jin, Jianping; Nystad, Wenche; Page, Christian M; Magnus, Maria; Jima, Dereje D; Hoyo, Cathrine; Maguire, Rachel L; Kvist, Tuomas; Czamara, Darina; Räikkönen, Katri; Gong, Tong; Ullemar, Vilhelmina; Rifas-Shiman, Sheryl L; Oken, Emily; Almqvist, Catarina; Karlsson, Robert; Lahti, Jari; Murphy, Susan K; Håberg, Siri E; London, Stephanie; Herberth, Gunda; Arshad, Hasan; Sunyer, Jordi; Grazuleviciene, Regina; Dabelea, Dana; Steegers-Theunissen, Régine PM; Nohr, Ellen A; Sørensen, Thorkild IA; Duijts, Liesbeth; Hivert, Marie-France; Nelen, Vera; Popovic, Maja; Kogevinas, Manolis; Nawrot, Tim S; Herceg, Zdenko; Annesi-Maesano, Isabella; Fallin, M Daniele; Yeung, Edwina; Breton, Carrie V; Koletzko, Berthold; Holland, Nina; Wiemels, Joseph L; Melén, Erik; Sharp, Gemma C; Silver, Matt J; Rezwan, Faisal I; Holloway, John W

    Background

    Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.

    Methods

    We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.

    Results

    We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).

    Conclusions

    In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.
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    ItemOpen Access
    DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study.
    (Environmental health perspectives, 2021-05-19) Fuemmeler, Bernard F; Dozmorov, Mikhail G; Do, Elizabeth K; Zhang, Junfeng Jim; Grenier, Carole; Huang, Zhiqing; Maguire, Rachel L; Kollins, Scott H; Hoyo, Cathrine; Murphy, Susan K

    Background

    Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.

    Objective

    This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.

    Methods

    Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 ng/mL to <4 ng/mL), and offspring epigenetic data from umbilical cord blood were included in this study (n=79). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any 1-ng/mL unit increase in exposure.

    Results

    Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population (n=115), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, estimate=-1.09, standard error (SE)=0.45, p=0.018) but not for AGER (cg09199225; estimate=-0.16, SE=0.21, p=0.44).

    Discussion

    Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099.
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    Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States.
    (BMC cancer, 2023-11) Bukowski, Alexandra; Hoyo, Cathrine; Vielot, Nadja A; Graff, Misa; Kosorok, Michael R; Brewster, Wendy R; Maguire, Rachel L; Murphy, Susan K; Nedjai, Belinda; Ladoukakis, Efthymios; North, Kari E; Smith, Jennifer S

    Background

    Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test.

    Methods

    A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05.

    Results

    At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP.

    Conclusions

    Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs.

    Impact

    Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.
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    Maternal blood cadmium, lead and arsenic levels, nutrient combinations, and offspring birthweight.
    (BMC Public Health, 2017-04-24) Luo, Yiwen; McCullough, Lauren E; Tzeng, Jung-Ying; Darrah, Thomas; Vengosh, Avner; Maguire, Rachel L; Maity, Arnab; Samuel-Hodge, Carmen; Murphy, Susan K; Mendez, Michelle A; Hoyo, Cathrine
    BACKGROUND: Cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants that have been associated with lower birthweight. Although some essential metals may mitigate exposure, data are inconsistent. This study sought to evaluate the relationship between toxic metals, nutrient combinations and birthweight among 275 mother-child pairs. METHODS: Non-essential metals, Cd, Pb, As, and essential metals, iron (Fe), zinc (Zn), selenium (Se), copper (Cu), calcium (Ca), magnesium (Mg), and manganese (Mn) were measured in maternal whole blood obtained during the first trimester using inductively coupled plasma mass spectrometry. Folate concentrations were measured by microbial assay. Birthweight was obtained from medical records. We used quantile regression to evaluate the association between toxic metals and nutrients due to their underlying wedge-shaped relationship. Ordinary linear regression was used to evaluate associations between birth weight and toxic metals. RESULTS: After multivariate adjustment, the negative association between Pb or Cd and a combination of Fe, Se, Ca and folate was robust, persistent and dose-dependent (p < 0.05). However, a combination of Zn, Cu, Mn and Mg was positively associated with Pb and Cd levels. While prenatal blood Cd and Pb were also associated with lower birthweight. Fe, Se, Ca and folate did not modify these associations. CONCLUSION: Small sample size and cross-sectional design notwithstanding, the robust and persistent negative associations between some, but not all, nutrient combinations with these ubiquitous environmental contaminants suggest that only some recommended nutrient combinations may mitigate toxic metal exposure in chronically exposed populations. Larger longitudinal studies are required to confirm these findings.
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    Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.
    (Hum Mol Genet, 2017-10-15) Sharp, Gemma C; Salas, Lucas A; Monnereau, Claire; Allard, Catherine; Yousefi, Paul; Everson, Todd M; Bohlin, Jon; Xu, Zongli; Huang, Rae-Chi; Reese, Sarah E; Xu, Cheng-Jian; Baïz, Nour; Hoyo, Cathrine; Agha, Golareh; Roy, Ritu; Holloway, John W; Ghantous, Akram; Merid, Simon K; Bakulski, Kelly M; Küpers, Leanne K; Zhang, Hongmei; Richmond, Rebecca C; Page, Christian M; Duijts, Liesbeth; Lie, Rolv T; Melton, Phillip E; Vonk, Judith M; Nohr, Ellen A; Williams-DeVane, ClarLynda; Huen, Karen; Rifas-Shiman, Sheryl L; Ruiz-Arenas, Carlos; Gonseth, Semira; Rezwan, Faisal I; Herceg, Zdenko; Ekström, Sandra; Croen, Lisa; Falahi, Fahimeh; Perron, Patrice; Karagas, Margaret R; Quraishi, Bilal M; Suderman, Matthew; Magnus, Maria C; Jaddoe, Vincent WV; Taylor, Jack A; Anderson, Denise; Zhao, Shanshan; Smit, Henriette A; Josey, Michele J; Bradman, Asa; Baccarelli, Andrea A; Bustamante, Mariona; Håberg, Siri E; Pershagen, Göran; Hertz-Picciotto, Irva; Newschaffer, Craig; Corpeleijn, Eva; Bouchard, Luigi; Lawlor, Debbie A; Maguire, Rachel L; Barcellos, Lisa F; Davey Smith, George; Eskenazi, Brenda; Karmaus, Wilfried; Marsit, Carmen J; Hivert, Marie-France; Snieder, Harold; Fallin, M Daniele; Melén, Erik; Munthe-Kaas, Monica C; Arshad, Hasan; Wiemels, Joseph L; Annesi-Maesano, Isabella; Vrijheid, Martine; Oken, Emily; Holland, Nina; Murphy, Susan K; Sørensen, Thorkild IA; Koppelman, Gerard H; Newnham, John P; Wilcox, Allen J; Nystad, Wenche; London, Stephanie J; Felix, Janine F; Relton, Caroline L
    Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.
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    ItemOpen Access
    Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.
    (Molecular psychiatry, 2023-12) Choudhary, Priyanka; Monasso, Giulietta S; Karhunen, Ville; Ronkainen, Justiina; Mancano, Giulia; Howe, Caitlin G; Niu, Zhongzheng; Zeng, Xuehuo; Guan, Weihua; Dou, John; Feinberg, Jason I; Mordaunt, Charles; Pesce, Giancarlo; Baïz, Nour; Alfano, Rossella; Martens, Dries S; Wang, Congrong; Isaevska, Elena; Keikkala, Elina; Mustaniemi, Sanna; Thio, Chris HL; Fraszczyk, Eliza; Tobi, Elmar W; Starling, Anne P; Cosin-Tomas, Marta; Urquiza, Jose; Röder, Stefan; Hoang, Thanh T; Page, Christian; Jima, Dereje D; House, John S; Maguire, Rachel L; Ott, Raffael; Pawlow, Xenia; Sirignano, Lea; Zillich, Lea; Malmberg, Anni; Rauschert, Sebastian; Melton, Phillip; Gong, Tong; Karlsson, Robert; Fore, Ruby; Perng, Wei; Laubach, Zachary M; Czamara, Darina; Sharp, Gemma; Breton, Carrie V; Schisterman, Enrique; Yeung, Edwina; Mumford, Sunni L; Fallin, M Daniele; LaSalle, Janine M; Schmidt, Rebecca J; Bakulski, Kelly M; Annesi-Maesano, Isabella; Heude, Barbara; Nawrot, Tim S; Plusquin, Michelle; Ghantous, Akram; Herceg, Zdenko; Nisticò, Lorenza; Vafeiadi, Marina; Kogevinas, Manolis; Vääräsmäki, Marja; Kajantie, Eero; Snieder, Harold; Corpeleijn, Eva; Steegers-Theunissen, Regine PM; Yang, Ivana V; Dabelea, Dana; Fossati, Serena; Zenclussen, Ana C; Herberth, Gunda; Magnus, Maria; Håberg, Siri E; London, Stephanie J; Munthe-Kaas, Monica Cheng; Murphy, Susan K; Hoyo, Cathrine; Ziegler, Anette-G; Hummel, Sandra; Witt, Stephanie H; Streit, Fabian; Frank, Josef; Räikkönen, Katri; Lahti, Jari; Huang, Rae-Chi; Almqvist, Catarina; Hivert, Marie-France; Jaddoe, Vincent WV; Järvelin, Marjo-Riitta; Kantomaa, Marko; Felix, Janine F; Sebert, Sylvain
    Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.