Cohort profile: Epigenetics in Pregnancy (EPIPREG) – population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes

Abstract

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother’s and child’s health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.

DNA Methylation in Gestational Diabetes and its Predictive Value for Postpartum Glucose Disturbances

“…Global DNAm is altered during hyperglycemia ( 34 , 35 ), and increased global methylation in placental tissue has been associated with GDM ( 36 , 37 ). However, there are limited data describing DNAm in the peripheral blood of patients with GDM, and the results are inconclusive ( 16-19 , 21 , 22 , 38 , 39 ). Small sample sizes and the absence of reproducibility or confirmatory cohorts have been the main weaknesses in most studies ( 16-18 , 38 ).…”

“…In a recent study on Black South African women, global DNAm in peripheral blood was found not to be associated with GDM, which was contrary to the authors’ hypothesis ( 20 ). Two studies with larger cohorts have been recently published using the Infinium MethylationEPIC BeadChip ( 21 , 22 ), which covers 850 000 CpG sites. Fragoso-Bargas et al ( 22 ) identified 4 CpG sites associated with BMI and hyperglycemia in peripheral blood leukocytes of a subcohort of the EPI-PREG study; however, the data were not validated in an independent cohort.…”

“…Two studies with larger cohorts have been recently published using the Infinium MethylationEPIC BeadChip ( 21 , 22 ), which covers 850 000 CpG sites. Fragoso-Bargas et al ( 22 ) identified 4 CpG sites associated with BMI and hyperglycemia in peripheral blood leukocytes of a subcohort of the EPI-PREG study; however, the data were not validated in an independent cohort. Canouil et al ( 21 ) used the same array to assess maternal methylation in a group of the FinnGeDi prospective multicenter cohort, but failed to find any significant differentially methylated positions associated with GDM (after false discovery rate adjustment) in an epigenome-wide association study.…”

Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes

“…Technical validation was performed on four CpG sites preliminary associated with fasting glucose, 2-hour glucose and BMI. Overall, the four sites had a good agreement between pyrosequencing and the EPIC array [15].…”

“…We have previously assessed genetic ethnic origin through ancestry principal component analysis by using the variance-standardized relationship matrix using PLINK 1.9. There was a clear separation between EUR and SA which corresponded to their inferred ancestry [15]. We, therefore, use self-reported ancestry for the categorization of ethnicity.…”