Accounting for Life-Course Exposures in Epigenetic Biomarker Association Studies: Early Life Socioeconomic Position, Candidate Gene DNA Methylation, and Adult Cardiometabolic Risk

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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Associations between indicators of socioeconomic position and DNA methylation: A systematic review

10.1101/2021.01.21.21250199 ◽

2021 ◽

Author(s):

Janine K. Cerutti ◽

Alexandre A. Lussier ◽

Yiwen Zhu ◽

Jiaxuan Liu ◽

Erin C. Dunn

Keyword(s):

Systematic Review ◽

Dna Methylation ◽

Life Course ◽

Socioeconomic Position ◽

Prenatal Development ◽

Future Research ◽

Socioeconomic Environment ◽

The Life Course ◽

Study Designs

AbstractSocioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term health. To understand the evidence supporting a potential SEP-DNAm link, we performed a systematic review of published empirical findings on the association between SEP (from prenatal development to adulthood) and DNAm measured across the life course, with an eye toward evaluating how the timing, duration, and type of SEP exposure influenced DNAm. Across the 37 studies we identified, there was some evidence for the effect of SEP timing and duration on DNAm, with early-life SEP and persistently low SEP being particularly strong indicators of DNAm. Different indicators of SEP also had some unique associations with DNAm profiles, suggesting that SEP is not a singular concept, but rather that different aspects of the socioeconomic environment can shift DNAm patterns through distinct pathways. These differences with respect to SEP timing, duration, and type were notable because they were detected even among heterogenous study designs. Overall, findings from this review underscore the importance of analyzing SEP timing, duration, and type, given the complex relationship between SEP and DNAm across the lifespan. To guide future research, we highlight current limitations in the literature and propose recommendations for overcoming some of these challenges.

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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Nature Communications ◽

10.1038/s41467-021-27198-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Adrienne Tin ◽

Pascal Schlosser ◽

Pamela R. Matias-Garcia ◽

Chris H. L. Thio ◽

Roby Joehanes ◽

...

Keyword(s):

Dna Methylation ◽

Complex Traits ◽

Cardiometabolic Risk ◽

Association Studies ◽

Meta Analysis ◽

Elevated Serum ◽

Complex Trait ◽

Serum Urate ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

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Socioeconomic Position and DNA Methylation Age Acceleration Across the Life Course

American Journal of Epidemiology ◽

10.1093/aje/kwy155 ◽

2018 ◽

Vol 187 (11) ◽

pp. 2346-2354 ◽

Cited By ~ 22

Author(s):

Amanda Hughes ◽

Melissa Smart ◽

Tyler Gorrie-Stone ◽

Eilis Hannon ◽

Jonathan Mill ◽

...

Keyword(s):

Dna Methylation ◽

Life Course ◽

Socioeconomic Position ◽

Dna Methylation Age ◽

The Life Course

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A multi-omics approach to investigate the inflammatory response to life course socioeconomic position

Epigenomics ◽

10.2217/epi-2019-0261 ◽

2020 ◽

Vol 12 (15) ◽

pp. 1287-1302

Author(s):

Raphaële Castagné ◽

Michelle Kelly-Irving ◽

Vittorio Krogh ◽

Domenico Palli ◽

Salvatore Panico ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Inflammatory Response ◽

Life Course ◽

Socioeconomic Position ◽

Protein Level ◽

Inflammatory Biomarkers ◽

Bonferroni Correction ◽

Cis Acting ◽

Prospective Investigation

Aim: Inflammation represents a potential pathway through which socioeconomic position (SEP) is biologically embedded. Materials & methods: We analyzed inflammatory biomarkers in response to life course SEP by integrating multi-omics DNA-methylation, gene expression and protein level in 178 European Prospective Investigation into Cancer and Nutrition-Italy participants. Results & conclusion: We identified 61 potential cis acting CpG loci whose methylation levels were associated with gene expression at a Bonferroni correction. We examined the relationships between life course SEP and these 61 cis-acting regulatory methylation sites individually and jointly using several scores. Less-advantaged SEP participants exhibit, later in life, a lower inflammatory methylome score, suggesting an overall increased expression of the corresponding inflammatory genes or proteins, supporting the hypothesis that SEP impacts adult physiology through inflammation.

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Associations between indicators of socioeconomic position and DNA methylation: a scoping review

Clinical Epigenetics ◽

10.1186/s13148-021-01189-0 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Janine Cerutti ◽

Alexandre A. Lussier ◽

Yiwen Zhu ◽

Jiaxuan Liu ◽

Erin C. Dunn

Keyword(s):

Dna Methylation ◽

Life Course ◽

Scoping Review ◽

Socioeconomic Position ◽

Prenatal Development ◽

Future Research ◽

Socioeconomic Environment ◽

The Life Course ◽

The Relationship ◽

Epigenetic Processes

Abstract Background Socioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possibility widely pursued in the scientific literature is that SEP becomes biologically embedded through epigenetic processes such as DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity in ways that shape health. Methods To understand the evidence supporting a potential SEP-DNAm link, we performed a scoping review of published empirical findings on the association between SEP assessed from prenatal development to adulthood and DNAm measured across the life course, with an emphasis on exploring how the developmental timing, duration, and type of SEP exposure influenced DNAm. Results Across the 37 identified studies, we found that: (1) SEP-related DNAm signatures varied across the timing, duration, and type of SEP indicator; (2) however, longitudinal studies examining repeated SEP and DNAm measures are generally lacking; and (3) prior studies are conceptually and methodologically diverse, limiting the interpretability of findings across studies with respect to these three SEP features. Conclusions Given the complex relationship between SEP and DNAm across the lifespan, these findings underscore the importance of analyzing SEP features, including timing, duration, and type. To guide future research, we highlight additional research gaps and propose four recommendations to further unravel the relationship between SEP and DNAm.

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