Jingxiong Xu1,2, Jean Shin1, Meghan McGee3, Sharon Unger4,5,6,7, Nicole Bando1,4, Julie Sato8,9,10, Marlee Vandewouw8,10,11,12, Yash Patel13, Helen M Branson14,15, Tomas Paus9,13,16,17,18, Zdenka Pausova1,4,19, Deborah L O'Connor1,4,6. 1. Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada. 2. Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada. 3. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 4. Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. 5. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. 6. Department of Pediatrics, Sinai Health, Toronto, Ontario, Canada. 7. Division of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada. 8. Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada. 9. Department of Psychology, University of Toronto, Toronto, Ontario, Canada. 10. Neuroscience & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada. 11. Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada. 12. Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. 13. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. 14. Division of Neuroradiology, Department of Medical Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada. 15. Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada. 16. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 17. Department of Psychiatry, Faculty of Medicine and CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada. 18. Department of Neuroscience, Faculty of Medicine and CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada. 19. Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.
BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.
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