Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data

Ross, Jason P.; Dijk, Susan van; Phang, Melinda; Skilton, Michael R.; Molloy, Peter L.; Oytam, Yalchin

doi:10.1186/s13148-022-01277-9

Cited by 19 publications

(23 citation statements)

References 85 publications

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“…Then, for our rst aim, the series of methylation values for each mother was correlated with the corresponding methylation values in her child across the whole epigenome, producing a motherchild Methylation similarity index (MSI) for each familial pair. Since the mother and child were measured in the same slide, this procedure controls for potential biases introduced by the experimental design (i.e., batch effects [41] ). We also correlated methylation values across the whole epigenome in randomly paired mother and child for all possible random mother-child pairs in the same experimental slide.…”

Section: Discussionmentioning

confidence: 99%

Mother adversity and co-residence time impact mother-child similarity in genome-wide and gene-specific methylation profiles

Labaut-Peñalver,

Lage-Castellanos,

Rodrigo

et al. 2024

Preprint

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Background. The effects of adverse life events on physical and psychological health, with DNA methylation (DNAm) as a critical underlying mechanism, have been extensively studied. However, the epigenetic resemblance between mother and child in the context of neglectful caregiving, and whether it may be shaped by the emotional impact of maternal stressful events and the duration of co-residence (indexed by child age), remains unknown. The present study examined mother-child similarity in methylation profiles, considering the potential effect of mother adversity, mother empathy, neglect-control group, child age (an index of years of mother-child co-residence), and mother age. We quantified DNAm in 115 mother-child saliva samples and obtained a methylation similarity index by computing correlation coefficients between methylation profiles within dyads, for the entire epigenome, and five specific genes related to stress and empathy: NR3C1, FKPB5, OXTR, SCL6A4, and BDNF. Results. The methylation profiles of the mother-child familial pairs significantly correlated as compared to mother-child random pairs for the entire epigenome and NR3C1, FKBP5, OXTR and BDNF genes. Next, multiple linear regression models observed associations of mother adversity, child age, and neglect-control group on mother-child methylation similarity, only significant in mother-child familial pairs, after correcting for multiple comparisons. Higher mother adversity was associated with lower mother-child methylation similarity for the epigenome-wide analysis, for the BDNF gene, and in the neglect-control group for the OXTR gene. In turn, being an older child (longer co-residence) was associated with higher mother-child methylation similarity. Conclusions. Mother adversity and co-residence time are modulating factors in the intergenerational methylation process that offer a window into development-dependent adaptations that can be affected by both hereditary and environmental factors, significantly observed only in biological dyads. A twofold implication for child well-being emerges, one is positive in that children of mothers exposed to life adversity or neglect did not necessarily inherit their methylation patterns. The other is worrisome, since the time living together is a crucial environmental factor with a high impact on epigenetic transmission in children, reinforcing the need for “the earlier, the better” recommendation of the Child Protection System, which is not always followed.

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Section: Discussionmentioning

confidence: 99%

Mother adversity and co-residence time impact mother-child similarity in genome-wide and gene-specific methylation profiles

Labaut-Peñalver,

Lage-Castellanos,

Rodrigo

et al. 2024

Preprint

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“…First, to our knowledge there are no comprehensive DNA methylation data that characterize the biologic foundation of DN progression. While there are many ways to assess DNA methylation, initial forays into diabetes were made using array hybridization and endonuclease digestion assays ( 39 , 40 ). In this study, to interpret the FinnDiane methylome, we considered that the genome coverage of various methodologies was critical to understanding the influence of methylation on gene function.…”

Section: Discussionmentioning

confidence: 99%

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes

Khurana¹,

Kaipananickal²,

Maxwell³

et al. 2023

Journal of Clinical Investigation

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Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome wide methylation patterns are poorly defined. While methylation is known to alter gene expression the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low.To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n=39) that was subsequently replicated in a larger validation cohort (n=296). Gene body related regions made up >60% of the methylation differences and emphasised the importance of methylation sequencing. We observe differentially methylated genes associated with DN (DDN) in three independent T1D registries originating from Denmark (n=445), Hong Kong (n=107) and Thailand (n=130). Reduced DNA methylation at CTCF and Pol2B sites were tightly connected with DN pathways that include insulin signalling, lipid metabolism and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubules. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding and the activation of insulin signalling phosphoproteins in hyperglycaemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophage and vascular endothelial cells.

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“…Functional normalization, a method that used the internal control probes present on the array to infer between array-technical variation and that extends quantile normalization and outperforms other types of normalization previously used [ 86 ] was carried out. Also, dye correction and normal-exponential out-of-band (NOOB) background correction were applied [ 87 ]. Beta-values (ranging from 0 to 1 and) were obtained as metrics to measure methylation levels and are based on the measured intensities of the pair of probes (a methylated probe and an unmethylated probe) at each CpG site [ 88 ].…”

Section: Methodsmentioning

confidence: 99%

DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet

Fernández-Carrión

Sorlí

Asensio

et al. 2023

IJERPH

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Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p = 2.2 × 10−32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.

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Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data

Cited by 19 publications

References 85 publications

Mother adversity and co-residence time impact mother-child similarity in genome-wide and gene-specific methylation profiles

Mother adversity and co-residence time impact mother-child similarity in genome-wide and gene-specific methylation profiles

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes

DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet

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