Within-subject changes in methylome profile identify individual signatures of early-life adversity, with a potential to predict neuropsychiatric outcome.

Autor:	Short AK; Department of Anatomy and Neurobiology, University of California- Irvine, Irvine, CA 92697.; Departments of Pediatrics and Neurology, University of California-Irvine, Irvine, CA, 92697.; Brain Tumour Research Program, Telethon Kids Institute, Nedlands, WA, Australia, 6009 (current).; Division of Paediatrics/Centre for Child Health Research, Medical School, University of Western Australia, Crawley, WA, Australia, 6009 (current)., Weber R; Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA 92697., Kamei N; Department of Anatomy and Neurobiology, University of California- Irvine, Irvine, CA 92697., Thai CW; Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA 92697., Arora H; Department of Statistics, University of California-Irvine, Irvine, CA, 92697., Mortazavi A; Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA 92697., Stern HS; Department of Statistics, University of California-Irvine, Irvine, CA, 92697., Glynn L; Department of Psychology, Chapman University, Orange, CA, 92866., Baram TZ; Department of Anatomy and Neurobiology, University of California- Irvine, Irvine, CA 92697.; Departments of Pediatrics and Neurology, University of California-Irvine, Irvine, CA, 92697.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 19. Date of Electronic Publication: 2023 Dec 19.
DOI:	10.1101/2023.12.16.571594
Abstrakt:	Background: Adverse early-life experiences (ELA), including poverty, trauma and neglect, affect a majority of the world's children. Whereas the impact of ELA on cognitive and emotional health throughout the lifespan is well-established, it is not clear how distinct types of ELA influence child development, and there are no tools to predict for an individual child their vulnerability or resilience to the consequences of ELAs. Epigenetic markers including DNA-methylation profiles of peripheral cells may encode ELA and provide a predictive outcome marker. However, the rapid dynamic changes in DNA methylation in childhood and the inter-individual variance of the human genome pose barriers to identifying profiles predicting outcomes of ELA exposure. Here, we examined the relation of several dimensions of ELA to changes of DNA methylation, using a longitudinal within-subject design and a high threshold for methylation changes in the hope of mitigating the above challenges. Methods: We analyzed DNA methylation in buccal swab samples collected twice for each of 110 infants: neonatally and at 12 months. We identified CpGs differentially methylated across time, calculated methylation changes for each child, and determined whether several indicators of ELA associated with changes of DNA methylation for individual infants. We then correlated select dimensions of ELA with methylation changes as well as with measures of executive function at age 5 years. We examined for sex differences, and derived a sex-dependent 'impact score' based on sites that most contributed to the methylation changes. Findings: Setting a high threshold for methylation changes, we discovered that changes in methylation between two samples of an individual child reflected age-related trends towards augmented methylation, and also correlated with executive function years later. Among the tested factors and ELA dimensions, including income to needs ratios, maternal sensitivity, body mass index and sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, an interaction was observed between a measure of high early-life unpredictability and methylation changes, in presaging executive function. Interpretation: These findings establish longitudinal, within-subject changes in methylation profiles as a signature of some types of ELA in an individual child. Notably, such changes are detectable beyond the age-associated DNA methylation dynamics. Future studies are required to determine if the methylation profile changes identified here provide a predictive marker of vulnerabilities to poorer cognitive and emotional outcomes. Competing Interests: Declaration of interests The authors declare no conflicts of interest.
Databáze:	MEDLINE
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