The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

Carreras-Gallo, Natàlia; Cáceres, Alejandro; Balagué-Dobón, Laura; Ruiz‐Arenas, Carlos; Andrušaitytė, Sandra; Carracedo, Ángel; Casas, Maribel; Chatzi, Leda; Gražulevičienė, Regina; Gützkow, Kristine B.; Lepeule, Johanna; Maitre, Léa; Nieuwenhuijsen, Mark; Slama, Rémy; Stratakis, Nikos; Thomsen, Cathrine; Urquiza, José; Wright, John; Yang, Tiffany; Escaramís, Geòrgia; Vrijheid, Martine; Pérez-Jurado, Luís A.; González, Juan R.

doi:10.1038/s42003-022-03380-2

Cited by 11 publications

(5 citation statements)

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“…Choi et al 11 stratified the ExWAS by polygenic risk scores of major depression and found that some significant factors in the full sample became null in the genetically at-risk sample. Another study suggested the multiple modulation pathways by exposure to DNA methylation, through numerous testing, regarded as the G×E-WAS 22 . Additionally, previous twin studies found geographic confounding in the assessment of A, C, and E variance, possibly attributable to differences in genetic ancestry.…”

Section: Discussionmentioning

confidence: 99%

Systematic evaluation of the environmental effect on depressive symptoms in late adolescence and early adulthood: exposome-wide association study and twin modeling

Wang

Zellers

Whipp

et al. 2023

Preprint

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The exposome represents the totality of environmental effects, but systematic evaluation between it and depressive symptoms is scant. We sought to comprehensively identify the association of the exposome with depressive symptoms in late adolescence and early adulthood and determine genetic and environmental covariances between them. Based on the population-based FinnTwin12 cohort (3025 participants in young adulthood and 4127 at age 17), the exposome-wide association study (ExWAS) design was used to identify significant exposures from 12 domains. Bivariate Cholesky twin models were fitted to an exposome score and depressive symptoms. In ExWASes, 29 and 46 exposures were significantly associated with depressive symptoms in young adulthood and at age 17, respectively, and family-related exposures were the most influential. Twin models indicated considerable genetic and environmental covariances between the exposome score and depressive symptoms. The findings underscore the systematic approach of the exposome and the consideration of relevant genetic effects.

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Section: Discussionmentioning

confidence: 99%

Systematic evaluation of the environmental effect on depressive symptoms in late adolescence and early adulthood: exposome-wide association study and twin modeling

Wang

Zellers

Whipp

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…DNA methylation was assessed using the Infinium Human Methylation 450 beadchip (Illumina), following the manufacturer’s protocol. Preprocessing of methylation data has been described elsewhere [ 34 ]. After sample and probe quality control measures, the number of CpG probes analyzed was 371,533, initially available for 1192 subjects.…”

Section: Methodsmentioning

confidence: 99%

Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

Cáceres

Carreras-Gallo

Andrušaitytė

et al. 2023

BMC Med

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Background Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children’s obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5–11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results We observed that E1 was defined by the combination of low dairy consumption, non-smokers’ cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction = 0.070, P = 2.59 × 10−5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction = 0.42, P = 0.047) and working memory (ORinteraction = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.

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“…Both DNA methylation and genotype are required to determine the pluripotency of induced stem cells 4 and their maturation capacity 5 . Germline genetic alterations cause changes in DNA methylation that ultimately dictate predisposition for disease 6 – 8 . Combining information on DNA methylation with genetic sequence in cell-free DNA (cfDNA) from blood has been shown to substantially increase sensitivity to detect tumor DNA 9 .…”

Section: Mainmentioning

confidence: 99%

Simultaneous sequencing of genetic and epigenetic bases in DNA

et al. 2023

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DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases fail to capture common C-to-T mutations or distinguish 5-methylcytosine from 5-hydroxymethylcytosine. We present a single base-resolution sequencing methodology that sequences complete genetics and the two most common cytosine modifications in a single workflow. DNA is copied and bases are enzymatically converted. Coupled decoding of bases across the original and copy strand provides a phased digital readout. Methods are demonstrated on human genomic DNA and cell-free DNA from a blood sample of a patient with cancer. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. Simultaneous, phased reading of genetic and epigenetic bases provides a more complete picture of the information stored in genomes and has applications throughout biomedicine.

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The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

Cited by 11 publications

References 88 publications

Systematic evaluation of the environmental effect on depressive symptoms in late adolescence and early adulthood: exposome-wide association study and twin modeling

Systematic evaluation of the environmental effect on depressive symptoms in late adolescence and early adulthood: exposome-wide association study and twin modeling

Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment

Simultaneous sequencing of genetic and epigenetic bases in DNA

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