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Epigenomics Volume 13, 2021 - Issue 24
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Research Article

Sex- and Tissue-Specific Effects of Binge-Level Prenatal Alcohol Consumption on DNA Methylation at Birth

Yuk Jing Loke1 Molecular Immunity, Murdoch Children’s Research Institute, Victoria, 3052, Australia;2 Department of Paediatrics, University of Melbourne, Victoria, 3010, AustraliaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0001-7966-8916View further author information
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Evelyne Muggli2 Department of Paediatrics, University of Melbourne, Victoria, 3010, Australia;3 Victorian Infant Brain Studies, Murdoch Children’s Research Institute, Victoria, 3052, Australia;5 Reproductive Epidemiology, Murdoch Children’s Research Institute, Victoria, 3052, AustraliaORCID Iconhttps://orcid.org/0000-0002-8102-9811View further author information
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Richard Saffery1 Molecular Immunity, Murdoch Children’s Research Institute, Victoria, 3052, Australia;2 Department of Paediatrics, University of Melbourne, Victoria, 3010, AustraliaORCID Iconhttps://orcid.org/0000-0002-9510-4181View further author information
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Joanne Ryan1 Molecular Immunity, Murdoch Children’s Research Institute, Victoria, 3052, Australia;4 Biological Neuropsychiatry & Dementia Unit, School of Public Health, Monash University, Victoria, 3004, AustraliaORCID Iconhttps://orcid.org/0000-0002-7039-6325View further author information
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Sharon Lewis2 Department of Paediatrics, University of Melbourne, Victoria, 3010, Australia;5 Reproductive Epidemiology, Murdoch Children’s Research Institute, Victoria, 3052, AustraliaORCID Iconhttps://orcid.org/0000-0001-6871-469XView further author information
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Elizabeth J Elliott6 Specialty of Child & Adolescent Health, Faculty of Medicine & Health, University of Sydney, NSW, 2050, Australia;7 The Australian Paediatric Surveillance Unit, Sydney Children’s Hospital Network, NSW, 2045, AustraliaORCID Iconhttps://orcid.org/0000-0002-6501-5487View further author information
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Jane Halliday2 Department of Paediatrics, University of Melbourne, Victoria, 3010, Australia;5 Reproductive Epidemiology, Murdoch Children’s Research Institute, Victoria, 3052, AustraliaORCID Iconhttps://orcid.org/0000-0001-6206-3857View further author information
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Jeffrey M Craig1 Molecular Immunity, Murdoch Children’s Research Institute, Victoria, 3052, Australia;2 Department of Paediatrics, University of Melbourne, Victoria, 3010, Australia;8 The Institute of Mental & Physical Health & Clinical Translation, Deakin University, Victoria, 3220, AustraliaORCID Iconhttps://orcid.org/0000-0003-3979-7849View further author information
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Pages 1921-1938 | Received 31 Jul 2021, Accepted 04 Nov 2021, Published online: 29 Nov 2021

Figures & data

Table 1. Comparison of maternal and infant characteristics between abstinent and binge PAE groups in buccal and placental samples.

Figure 1. Multidimensional scaling plots.

Multidimensional scaling plot of (A) buccal and (B) placenta datasets coloured according to sex. These plots illustrate that DNA methylation variation captured by principal component 6 and principal component 2 in buccal and placenta datasets, respectively, is largely attributed to sex (blue circles: male; red circles: female).

Figure 1. Multidimensional scaling plots.Multidimensional scaling plot of (A) buccal and (B) placenta datasets coloured according to sex. These plots illustrate that DNA methylation variation captured by principal component 6 and principal component 2 in buccal and placenta datasets, respectively, is largely attributed to sex (blue circles: male; red circles: female).
Figure 2. Heatmap of correlations between top principal components and covariates in both tissues of female and male data.

Pearson’s correlation coefficients are listed in each box, along with the p-values in brackets. Strength of correlation is annotated by the color legend. Covariates with a correlation coefficient > ±0.5 and p-values <0.05 were considered to be significantly associated with variation in DNA methylation. Cell type was highly correlated with the top principal components of interest in all groups.

AQoL: Assessment of quality of life; T: Trimester.

Figure 2. Heatmap of correlations between top principal components and covariates in both tissues of female and male data.Pearson’s correlation coefficients are listed in each box, along with the p-values in brackets. Strength of correlation is annotated by the color legend. Covariates with a correlation coefficient > ±0.5 and p-values <0.05 were considered to be significantly associated with variation in DNA methylation. Cell type was highly correlated with the top principal components of interest in all groups.AQoL: Assessment of quality of life; T: Trimester.
Figure 3. Multidimensional scaling plots of buccal dataset in male and female offspring colored based on ethnicity.

Multidimensional scaling plots illustrate that dataset of non-European origin samples (blue circles) are distinct from European origin samples (red circles), captured by (A) PC 3 for males and (B) PC 2 for females.

PC: Principal component.

Figure 3. Multidimensional scaling plots of buccal dataset in male and female offspring colored based on ethnicity.Multidimensional scaling plots illustrate that dataset of non-European origin samples (blue circles) are distinct from European origin samples (red circles), captured by (A) PC 3 for males and (B) PC 2 for females.PC: Principal component.
Figure 4. Potential differentially methylated regions identified in buccal DNA from female offspring.

(A) Overlapping line plots that depict a potential DMR. Solid and dotted lines denote average DNA methylation (beta) values of binge PAE and control groups respectively for probes annotated to chromosome 8 found within the 10 sum-of-ranked probes. Probes are ordered according to genomic position on the x-axis. The four probes in black boxes (cg23958373, cg07234876, cg26554054, cg15331088) are in the top 10 sum-of-ranked probes that clustered within 1000 bp. The gray box highlights the potential DMR. The two probes (cg05028639, cg24842815) marked with asterisks are the other top 10 differentially methylated probes mapped to ERICH1, 18.2 kb and 33.6 kb 3′ of the potential DMR. (B) Boxplots illustrating beta value differences between control and binge PAE groups of the four clustered probes in the top 10 sum-of-ranked probes. The thick lines in the boxes represent the median, the boxes represent data within the 25th and 75th percentile range, whiskers represent the 5th–95th percentile range. The circles are the outliers.

DMR: Differentially methylated region; PAE: Prenatal alcohol exposure.

Figure 4. Potential differentially methylated regions identified in buccal DNA from female offspring. (A) Overlapping line plots that depict a potential DMR. Solid and dotted lines denote average DNA methylation (beta) values of binge PAE and control groups respectively for probes annotated to chromosome 8 found within the 10 sum-of-ranked probes. Probes are ordered according to genomic position on the x-axis. The four probes in black boxes (cg23958373, cg07234876, cg26554054, cg15331088) are in the top 10 sum-of-ranked probes that clustered within 1000 bp. The gray box highlights the potential DMR. The two probes (cg05028639, cg24842815) marked with asterisks are the other top 10 differentially methylated probes mapped to ERICH1, 18.2 kb and 33.6 kb 3′ of the potential DMR. (B) Boxplots illustrating beta value differences between control and binge PAE groups of the four clustered probes in the top 10 sum-of-ranked probes. The thick lines in the boxes represent the median, the boxes represent data within the 25th and 75th percentile range, whiskers represent the 5th–95th percentile range. The circles are the outliers.DMR: Differentially methylated region; PAE: Prenatal alcohol exposure.

Table 2. Top 10 probes ranked by ‘sum of ranks’ in female buccal (n = 71) and placental (n = 51) datasets.

Figure 5. Potential differentially methylated regions identified in placental DNA from female offspring.

(A) Overlapping line plots that depict a potential DMR; solid and dotted lines denote average beta values of binge PAE and control groups respectively for probes annotated to chromosome 8 found within the top 10 sum-of-ranked probes. Probes are ordered according to genomic position on the x-axis. The three probes in black boxes (cg14745270, cg2751169, cg01197613) are in the top 10 sum-of-ranked probes that clustered within 1000 bp. The gray box highlights the potential DMR. (B) Boxplots illustrate beta value differences of between control and binge PAE groups of the three clustered probes in the top 10 sum-of-ranked probes. The thick lines in in the boxes represent the median, the boxes represent data within the 25th and 75th percentile range, whiskers represent the 5th–95th percentile range. The circles are the outliers.

DMR: Differentially methylated region; PAE: Prenatal alcohol exposure.

Figure 5. Potential differentially methylated regions identified in placental DNA from female offspring. (A) Overlapping line plots that depict a potential DMR; solid and dotted lines denote average beta values of binge PAE and control groups respectively for probes annotated to chromosome 8 found within the top 10 sum-of-ranked probes. Probes are ordered according to genomic position on the x-axis. The three probes in black boxes (cg14745270, cg2751169, cg01197613) are in the top 10 sum-of-ranked probes that clustered within 1000 bp. The gray box highlights the potential DMR. (B) Boxplots illustrate beta value differences of between control and binge PAE groups of the three clustered probes in the top 10 sum-of-ranked probes. The thick lines in in the boxes represent the median, the boxes represent data within the 25th and 75th percentile range, whiskers represent the 5th–95th percentile range. The circles are the outliers.DMR: Differentially methylated region; PAE: Prenatal alcohol exposure.

Table 3. Top 10 regions from DMRcate ranked by ‘minfdr’ in female buccal (n = 71) and placenta (n = 51) dataset.

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