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Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour.

Lillycrop KA, Costello PM, Teh AL, Murray RJ, Clarke-Harris R, Barton SJ, Garratt ES, Ngo S, Sheppard AM, Wong J, Dogra S, Burdge GC, Cooper C, Inskip HM, Gale CR, Gluckman PD, Harvey NC, Chong YS, Yap F, Meaney MJ, Rifkin-Graboi A, Holbrook JD, Epigen Global Research ConsortiumGodfrey KM - Int J Epidemiol (2015)

Bottom Line: Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds.Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success.Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biological Sciences, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK, kal@soton.ac.uk.

No MeSH data available.


Related in: MedlinePlus

HES1 DMROI methylation at birth is associated with childhood neuropsychological function. a) Association between cord HES1 CpG2 and CpG5 methylation and Wechsler Pre-School and Primary Scale of Intelligence (WPPSI IQ) at age 4 years. b) Association between cord HES1 CpG5 and CpG7 methylation and spatial span length at 7 years of age. c) Association between cord HES1 CpG 5 methylation and delayed matching to sample (DMS) 12 s delay total correct at 7 years of age. d) Association between cord HES1 CpG7 methylation and infant externalising score. Methylation has been divided into 4 equal groups according to rank; means and standard errors are plotted for each group. P-values are for regression of continuous variables adjusting for gender and mother’s IQ.
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dyv052-F3: HES1 DMROI methylation at birth is associated with childhood neuropsychological function. a) Association between cord HES1 CpG2 and CpG5 methylation and Wechsler Pre-School and Primary Scale of Intelligence (WPPSI IQ) at age 4 years. b) Association between cord HES1 CpG5 and CpG7 methylation and spatial span length at 7 years of age. c) Association between cord HES1 CpG 5 methylation and delayed matching to sample (DMS) 12 s delay total correct at 7 years of age. d) Association between cord HES1 CpG7 methylation and infant externalising score. Methylation has been divided into 4 equal groups according to rank; means and standard errors are plotted for each group. P-values are for regression of continuous variables adjusting for gender and mother’s IQ.

Mentions: We chose to validate HES1 since it has been shown to play an essential role in the generation of organising centres within the brain of the appropriate size, shape and specification by controlling the timing of cell differentiation within the CNS.16 Moreover, the region of HES1 identified as a DMROI was located 4.8 kb upstream of the transcription start site (TSS), in a region of HES1 that is evolutionarily conserved, suggesting that altered methylation of this region of HES1 may have important functional consequences for neuronal differentiation and function. Methylation levels of nine CpGs within this region were analysed by pyrosequencing in an extended sample of 175 SWS subjects (including the 24 samples used for the MBD array) for which 4-year WPPSI data were available. The concordance of methylation values with WPPSI scores for the 100 bp region within the HES1 ROI selected for pyrosequencing validation can be seen in Figure 2d. Consistent with these findings from the MBD array, associations were seen between the cord DNA methylation status of individual CpGs within the DMROI of HES1 and the child’s 4-year WPPSI IQ (Figure 3a). Higher percentage methylation of CpG2 associated with higher 4-year WPPSI IQ (β = 2.693, P = 0.009) with a trend for CpG5 (β = 1.951, P = 0.072, Table 1). Adjusting for the mother’s IQ strengthened associations between the percentage methylation of CpGs 2 and 5 and child’s IQ (β = 3.192, P = 0.002; β = 2.140, P = 0.045, respectively; Table 1); omitting the original 24 discovery samples from these analyses had little effect on the associations (e.g. for CpG 2 revised, β = 3.179, P = 0.005). Likewise, further adjustment for maternal smoking, BMI and parity and the child’s birthweight and age at WPPSI measurement had little effect on the magnitude and statistical significance of the association with CpG2, but for CpG5 there was an attenuation (Supplementary Table 6, available as Supplementary data at IJE online). The multivariate model combining HES1 CpG2, child’s IQ and maternal IQ explained 15.7% of the WPPSI variability; similar variability was explained by models replacing CpG2 with CpG5 or CpG7 methylation. The presence of SNPs at the identified CpG sites in HES1 were excluded by direct sequencing of this region.Figure 3.


Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour.

Lillycrop KA, Costello PM, Teh AL, Murray RJ, Clarke-Harris R, Barton SJ, Garratt ES, Ngo S, Sheppard AM, Wong J, Dogra S, Burdge GC, Cooper C, Inskip HM, Gale CR, Gluckman PD, Harvey NC, Chong YS, Yap F, Meaney MJ, Rifkin-Graboi A, Holbrook JD, Epigen Global Research ConsortiumGodfrey KM - Int J Epidemiol (2015)

HES1 DMROI methylation at birth is associated with childhood neuropsychological function. a) Association between cord HES1 CpG2 and CpG5 methylation and Wechsler Pre-School and Primary Scale of Intelligence (WPPSI IQ) at age 4 years. b) Association between cord HES1 CpG5 and CpG7 methylation and spatial span length at 7 years of age. c) Association between cord HES1 CpG 5 methylation and delayed matching to sample (DMS) 12 s delay total correct at 7 years of age. d) Association between cord HES1 CpG7 methylation and infant externalising score. Methylation has been divided into 4 equal groups according to rank; means and standard errors are plotted for each group. P-values are for regression of continuous variables adjusting for gender and mother’s IQ.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4588869&req=5

dyv052-F3: HES1 DMROI methylation at birth is associated with childhood neuropsychological function. a) Association between cord HES1 CpG2 and CpG5 methylation and Wechsler Pre-School and Primary Scale of Intelligence (WPPSI IQ) at age 4 years. b) Association between cord HES1 CpG5 and CpG7 methylation and spatial span length at 7 years of age. c) Association between cord HES1 CpG 5 methylation and delayed matching to sample (DMS) 12 s delay total correct at 7 years of age. d) Association between cord HES1 CpG7 methylation and infant externalising score. Methylation has been divided into 4 equal groups according to rank; means and standard errors are plotted for each group. P-values are for regression of continuous variables adjusting for gender and mother’s IQ.
Mentions: We chose to validate HES1 since it has been shown to play an essential role in the generation of organising centres within the brain of the appropriate size, shape and specification by controlling the timing of cell differentiation within the CNS.16 Moreover, the region of HES1 identified as a DMROI was located 4.8 kb upstream of the transcription start site (TSS), in a region of HES1 that is evolutionarily conserved, suggesting that altered methylation of this region of HES1 may have important functional consequences for neuronal differentiation and function. Methylation levels of nine CpGs within this region were analysed by pyrosequencing in an extended sample of 175 SWS subjects (including the 24 samples used for the MBD array) for which 4-year WPPSI data were available. The concordance of methylation values with WPPSI scores for the 100 bp region within the HES1 ROI selected for pyrosequencing validation can be seen in Figure 2d. Consistent with these findings from the MBD array, associations were seen between the cord DNA methylation status of individual CpGs within the DMROI of HES1 and the child’s 4-year WPPSI IQ (Figure 3a). Higher percentage methylation of CpG2 associated with higher 4-year WPPSI IQ (β = 2.693, P = 0.009) with a trend for CpG5 (β = 1.951, P = 0.072, Table 1). Adjusting for the mother’s IQ strengthened associations between the percentage methylation of CpGs 2 and 5 and child’s IQ (β = 3.192, P = 0.002; β = 2.140, P = 0.045, respectively; Table 1); omitting the original 24 discovery samples from these analyses had little effect on the associations (e.g. for CpG 2 revised, β = 3.179, P = 0.005). Likewise, further adjustment for maternal smoking, BMI and parity and the child’s birthweight and age at WPPSI measurement had little effect on the magnitude and statistical significance of the association with CpG2, but for CpG5 there was an attenuation (Supplementary Table 6, available as Supplementary data at IJE online). The multivariate model combining HES1 CpG2, child’s IQ and maternal IQ explained 15.7% of the WPPSI variability; similar variability was explained by models replacing CpG2 with CpG5 or CpG7 methylation. The presence of SNPs at the identified CpG sites in HES1 were excluded by direct sequencing of this region.Figure 3.

Bottom Line: Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds.Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success.Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biological Sciences, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK, kal@soton.ac.uk.

No MeSH data available.


Related in: MedlinePlus