Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Solomon, Olivia; Huena, Karen; Yousefi, Paul; Küpers, Leanne K.; González, Juan R.; Suderman, Matthew; Reese, Sarah E.; Page, Christian M.; Gruzieva, Olena; Rzehak, Peter; Gao, Lu; Bakulski, Kelly M.; Novoloaca, Alexei; Allard, Catherine; Pappa, Irene; Llambrich, Maria; Vives, Marta; Jima, Dereje D.; Kvist, Tuomas; Baccarelli, Andrea A.; White, Cory H.; Rezwan, Faisal I.; Sharp, Gemma C; Tindula, Gwen; Bergström, Anna; Grote, Veit; Dou, John; Isaevska, Elena; Magnus, Maria C; Corpeleijn, Eva; Perron, Patrice; Jaddoe, Vincent W.V.; Nøhr, Ellen A.; Maitre, Léa; Foraster, María; Hoyo, Cathrine; Håberg, Siri E.; Lahti, Jari; DeMeo, Dawn L.; Zhang, Hongmei; Karmaus, Wilfried; Kull, Inger; Koletzko, Berthold; Feinberg, Jason I.; Gagliardi, Luigi; Bouchard, Luigi; Ramlau‐Hansen, Cecilia Høst; Tiemeier, Henning; Santorelli, Gillian; Maguire, Rachel; Litonjua, Augusto A.; Langhendries, Jean‐Paul; Plusquin, Michelle; Lepeule, Johanna; Binder, Elisabeth B.; Verduci, Elvira; Dwyer, Terence; Carracedo, Ángel; Ferré, Natàlia; Eskenazi, Brenda; Kogevinas, Manolis; Nawrot, Tim S.; Munthe‐Kaas, Monica Cheng; Herceg, Zdenko; Relton, Caroline; Gruszfeld, Dariusz; Breton, Carrie V.; Fallin, M. Daniele; Ghantous, Akram; Nystad, Wenche; Heude, Barbara; Snieder, Harold; Hivert, Marie‐France; Felix, Janine F.; Sørensen, Thorkild I A; Murphy, Susan K.; Räikkönen, Katri; Oken, Emily; Holloway, John W.; Arshad, Syed Hasan; London, Stephanie J.; Holland, Nina

doi:10.1016/j.mrrev.2022.108415

Cited by 32 publications

(36 citation statements)

References 69 publications

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“…We observed inflated λ values in both SABRE ( λ = 2.93) and BiB ( λ = 2.22) EWAS. λ values were recalculated as described previously [ 45 ] (see methods). λ was substantially reduced in both SABRE ( λ = 1.53) and BiB ( λ = 1.02), indicating inflation is likely to stem from the abundance of the true biological signal rather than substantial residual confounding.…”

Section: Resultsmentioning

confidence: 99%

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Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans

et al. 2022

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Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently, there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts: Southall and Brent Revisited and Born in Bradford. DNA methylation differences between ethnicities were widespread throughout the genome (n = 16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity-associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.

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Section: Resultsmentioning

confidence: 99%

“…To investigate inflation of observed λ values we used a method described previously [ 45 ] where lambdas were recalculated in SABRE using CpGs which had p > 0.2 in the corresponding BiB EWAS and vice versa where lambdas were recalculated in BiB using CpGs which had p > 0.2 in the corresponding SABRE EWAS.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans

et al. 2022

Self Cite

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show abstract

“…We observed inflated λ values in both SABRE (λ=2.93) and BiB (λ=2.22) EWAS. λ values were recalculated described previously 39 (see methods). λ was substantially reduced in both SABRE (λ=1.53) and BiB (λ=1.02), indicating inflation is likely to stem from abundance of true biological signal rather than substantial residual confounding.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate inflation of observed λ values we used a method described previously 39 where lambdas were recalculated in SABRE using CpGs which had p>0.2 in the corresponding BiB EWAS and vice versa where lambdas were recalculated in BiB using CpGs which had p>0.2 in the corresponding SABRE EWAS.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of ethnic differences in DNA methylation between UK resident South Asians and Europeans

Elliott

Burrows

Min

et al. 2022

Preprint

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Ethnic differences in non-communicable disease risk have been described between individuals of South Asian and European ethnicity that are only partially explained by genetics and other known risk factors. DNA methylation is one underexplored mechanism that may explain differences in disease risk. Currently there is little knowledge of how DNA methylation varies between South Asian and European ethnicities. This study characterised differences in blood DNA methylation between individuals of self-reported European and South Asian ethnicity from two UK-based cohorts; Southall and Brent Revisited (SABRE) and Born in Bradford (BiB). DNA methylation differences between ethnicities were widespread throughout the genome (n=16,433 CpG sites, 3.4% sites tested). Specifically, 76% of associations were attributable to ethnic differences in cell composition with fewer effects attributable to smoking and genetic variation. Ethnicity associated CpG sites were enriched for EWAS Catalog phenotypes including metabolites. This work highlights the need to consider ethnic diversity in epigenetic research.

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“…A broad range of studies, based on the sex bias of prevalence of diseases and disorders, points to a sex-specific differences in stress response. We and others [ 29 , 30 ] have provided evidence of sex bias in cord blood DNA methylation. Recently McGill et al [ 6 ] showed that prenatal maternal anxiety predicted infant AA (PedBE algorithm) in two cohorts, independent of obstetric, socioeconomic, and genetic risk factors.…”

Section: Introductionmentioning

confidence: 96%

Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure

et al. 2022

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Background Physiological maternal stress response, such as imbalance in the glucocorticoid pathway and immune system seems to be mediated by DNA methylation (DNAm) and might translate intrauterine stress exposures into phenotypic changes in a sex-specific manner. DNAm in specific sites can also predict newborn gestational age and gestational age acceleration (GAA). GAA occurs when the predicted biological age is higher than the chronological age. In adults, poor health outcomes related to this deviance are well documented and raise questions for the interpretation and prediction in early stages of life. Boys seem to be more vulnerable to intrauterine stress exposure than girls; however, the mechanisms of adaptive sex-specific responses are still unclear. We hypothesize that intrauterine stress exposure is associated with GAA and could be different in boys and girls if inflammatory or glucocorticoid pathways exposure is considered. Results Using the Western Region Birth Cohort (ROC—São Paulo, Brazil) (n = 83), we calculated DNAm age and GAA from cord blood samples. Two epigenetic risk scores were calculated as an indirect proxy for low-grade inflammation (i-ePGS) and for glucocorticoid exposure (GES). Multivariate linear regression models were applied to investigate associations of GAA with prenatal exposures. The i-ePGS and GES were included in different models with the same co-variates considering sex interactions. The first multivariate model investigating inflammatory exposure (adj. R2 = 0.31, p = < 0.001) showed that GAA was positively associated with i-ePGS (CI, 0.26–113.87, p = 0.049) and negative pregnancy-related feelings (CI, 0.04–0.48 p = 0.019). No sex interaction was observed. The second model investigating glucocorticoid exposure (adj. R2 = 0.32, p = < 0.001) showed that the higher was the GAA was associated with a lower the lower was the GES in girls (CI, 0.04–2.55, p = 0.044). In both models, maternal self-reported mental disorder was negatively associated with GAA. Conclusion Prenatal epigenetic score of exposure to low-grade inflammatory was a predictor of GAA for both sexes. Glucocorticoid epigenetic score seems to be more important to GAA in girls. This study supports the evidence of sex-specificity in stress response, suggesting the glucocorticoid as a possible pathway adopted by girls to accelerate the maturation in an adverse condition.

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Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Cited by 32 publications

References 69 publications

Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans

Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans

Characterisation of ethnic differences in DNA methylation between UK resident South Asians and Europeans

Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure

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