DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood
Abstract
:1. Introduction
2. Materials and Methods
2.1. Overview
2.2. Subjects and Samples
2.2.1. Discovery Study
2.2.2. NTR Replication Study
2.2.3. ALSPAC Replication Study
2.3. Phenotype Data
ALSPAC Replication Study
2.4. DNA Sample Collection
2.4.1. NTR (Discovery and Replication Study)
2.4.2. ALSPAC Replication Study
2.5. DNA-Methylation Measurements
2.5.1. NTR Discovery Study
2.5.2. NTR Replication Study
2.5.3. ALSPAC Replication Study
2.6. Cellular Proportions
2.6.1. NTR Discovery and Replication Study
2.6.2. ALSPAC Replication Study
2.7. Data Analyses
2.7.1. Associations between Breastfeeding and Pre- and Perinatal Factors
2.7.2. EWAS
Discovery Study
Twin Correlations
Replication
2.8. Methylation Data Annotation
2.9. Overlap with Previous Findings
3. Results
3.1. Descriptive Statistics
3.2. Association Analysis Findings
3.3. Replication Analysis of Our Findings in Other Samples
3.4. Replication Analysis of Findings from Previous EWAS
3.5. Methylation Data Annotation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CpG | cytosine-phosphate-guanine |
EWAS | epigenome-wide association study |
NTR | Netherlands Twin Register |
ALSPAC | Avon Longitudinal Study of Parents and Children |
SES | socio-economic status |
GA | gestational age |
BMI | body mass index |
GEE | generalized estimating equations |
mQTL | methylation quantitative trait locus |
SNP | single nucleotide polymorphism |
MZ | monozygotic |
DZ | dizygotic |
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Breastfeeding Never (n = 265) | Breastfeeding Ever (n = 741) | Total | ||||
---|---|---|---|---|---|---|
n | % | n | % | n | % | |
Sex | ||||||
male | 138 | 52.1% | 349 | 47.1% | 487 | 48.4% |
female | 127 | 47.9% | 392 | 52.9% | 519 | 51.6% |
Zygosity | ||||||
Monozygotic (MZ) | 226 | 85.3% | 613 | 82.7% | 839 | 83.4% |
Dizygotic (DZ) | 39 | 14.7% | 128 | 17.3% | 167 | 16.6% |
Chorionicity | ||||||
MCMA | 4 | 3.5% | 21 | 7.3% | 25 | 6.2% |
MCDA | 61 | 53.0% | 144 | 50.3% | 205 | 51.1% |
DCDA | 50 | 43.5% | 121 | 42.3% | 171 | 42.6% |
Gestational Age (Weeks) | ||||||
Mean (SD) | 36.2 | (22.2) | 35.8 | (25.9) | 35.9 | (25.1) |
≤ 32 | 12 | 4.8% | 61 | 8.4% | 73 | 7.5% |
33–36 | 128 | 51.4% | 359 | 49.4% | 487 | 49.9% |
≥ 37 | 109 | 43.8% | 306 | 42.1% | 415 | 42.6% |
Mother’s Age at Birth (Years) | ||||||
Mean (SD) | 31.9 | (4.5) | 31.2 | (4.2) | 31.4 | (4.3) |
19–29 | 76 | 29.0% | 288 | 39.0% | 364 | 36.4% |
30–39 | 175 | 66.8% | 435 | 58.9% | 610 | 61.0% |
>40 | 11 | 4.2% | 15 | 2.0% | 26 | 2.6% |
Mother’s BMI Before Pregnancy | ||||||
Mean (SD) | 24.3 | (4.0) | 24.2 | (4.11) | 24.2 | (4.1) |
<25 | 149 | 61.3% | 470 | 66.1% | 619 | 64.9% |
25–29 | 70 | 28.8% | 169 | 23.8% | 239 | 25.1% |
30–39 | 24 | 9.9% | 65 | 9.1% | 89 | 9.3% |
>40 | 0 | 0.0% | 7 | 1.0% | 7 | 0.7% |
Father’s Age at Birth (Years) | ||||||
Mean (SD) | 33.2 | (4.4) | 33.9 | (5.4) | 33.7 | (5.2) |
20–29 | 53 | 22.0% | 146 | 20.3% | 199 | 20.8% |
30–39 | 163 | 67.6% | 482 | 67.1% | 645 | 67.3% |
>40 | 25 | 10.4% | 90 | 12.5% | 115 | 12.0% |
Mode of Conception | ||||||
naturally | 227 | 92.7% | 623 | 86.5% | 850 | 88.1% |
stimulated | 4 | 1.6% | 26 | 3.6% | 30 | 3.1% |
IVF/ICSI | 14 | 5.7% | 71 | 9.9% | 85 | 8.8% |
Maternal Smoking | ||||||
no smoking | 205 | 86.1% | 631 | 92.9% | 836 | 91.2% |
smoking | 33 | 13.9% | 48 | 7.1% | 81 | 8.8% |
Parental SES | ||||||
low skill level | 0 | 0.0% | 8 | 1.2% | 8 | 0.9% |
lower secondary educational level | 30 | 11.9% | 41 | 6.1% | 71 | 7.6% |
upper secondary education level | 99 | 39.3% | 203 | 30.0% | 302 | 32.5% |
higher vocational level | 89 | 35.3% | 234 | 34.6% | 323 | 34.8% |
scientific level | 34 | 13.5% | 191 | 28.2% | 225 | 24.2% |
Mode of Delivery | ||||||
vaginal | 141 | 56.6% | 416 | 57.1% | 557 | 57.0% |
caesarean planned | 43 | 17.3% | 97 | 13.3% | 140 | 14.3% |
urgent intervention (forceps, vacuum extraction) | 20 | 8.0% | 75 | 10.3% | 95 | 9.7% |
urgent caesarean section | 45 | 18.1% | 140 | 19.2% | 185 | 18.9% |
Birth Weight | ||||||
Mean (SD) | 2435.7 | (444.8) | 2394.6 | (558) | 2405 | (531.7) |
<1500 | 8 | 3.2% | 52 | 7.1% | 60 | 6.2% |
1500–2500 | 123 | 49.8% | 338 | 46.4% | 461 | 47.3% |
>2500 | 116 | 47.0% | 338 | 46.4% | 454 | 46.6% |
Apgar Score at 1st Minute | ||||||
0–6 | 17 | 12.3% | 48 | 12.8% | 65 | 12.7% |
7–9 | 103 | 74.6% | 290 | 77.5% | 393 | 76.8% |
10 | 18 | 13.0% | 36 | 9.6% | 54 | 10.5% |
Apgar Score at 5th Minute | ||||||
0–6 | 1 | 0.8% | 14 | 3.9% | 15 | 3.1% |
7–9 | 41 | 31.1% | 130 | 36.3% | 171 | 34.9% |
10 | 90 | 68.2% | 214 | 59.8% | 304 | 62.0% |
Breastfeeding Duration | ||||||
no | 265 | 100.0% | 0 | 265 | 26.3% | |
less than 2 weeks | 75 | 10.1% | 75 | 7.5% | ||
2–6 weeks | 189 | 25.5% | 189 | 18.8% | ||
6 weeks to 3 months | 181 | 24.4% | 181 | 18.0% | ||
3–6 months | 148 | 20.0% | 148 | 14.7% | ||
more than 6 months | 148 | 20.0% | 148 | 14.7% |
cgID | Chromosome | Position | Gene | Gene Region | Discovery Study | Discovery Study Without Outliers | ||||
---|---|---|---|---|---|---|---|---|---|---|
Estimate | SE | p-Value | Estimate | SE | p-Value | |||||
Basic Model (1). Sub-Sample < 10 years (n = 517) | ||||||||||
cg25178826 | chr5 | 35165447 | PRLR | 5’UTR | −0.026 | 0.004 | 8.04 × 10–12 | −6.04 × 10–5 | 0.001 | 0.98 |
cg12087956 | chr15 | 43022167 | CDAN1 | Body | −0.031 | 0.005 | 1.18 × 10–8 | 4.92 × 10–5 | 0.001 | 0.50 |
cg24192772 | chr17 | 80536920 | FOXK2 | Body | −0.024 | 0.004 | 2.52 × 10–8 | 9.17 × 10–4 | 0.001 | 0.15 |
cg10142656 | chr9 | 37753047 | TRMT10B | TSS1500 | −0.019 | 0.004 | 6.28 × 10–8 | 9.98 × 10–5 | 0.0007 | 0.14 |
Adjusted Model (2). Discovery Sample (n = 1006) | ||||||||||
cg22491379 | chr2 | 120553625 | PTPN4 | 5’UTR | −0.007 | 0.001 | 1.30 × 10–9 | −0.005 | 0.001 | 5.78 × 10–3 |
Adjusted Model (2). Sub-Sample < 10 Years (n = 517) | ||||||||||
cg03463465 | chr6 | 164143581 | 0.360 | 0.034 | 4.51 × 10–26 | −0.003 | 0.001 | 0.01 | ||
cg07670516 | chr17 | 5019840 | ZNF232 | 5’UTR | 0.249 | 0.032 | 1.40 × 10–14 | 0.006 | 0.014 | 0.65 |
cg20820810 | chr11 | 71850130 | FOLR3 | Body | −0.300 | 0.054 | 2.82 × 10–8 | −0.001 | 0.001 | 0.21 |
cg16279140 | chr14 | 103981749 | −0.411 | 0.052 | 3.50 × 10–15 | no outliers | ||||
cg05823759 | chr7 | 149646627 | 0.205 | 0.032 | 2.35 × 10–10 | no outliers | ||||
cg27284194 | chr4 | 1044797 | 0.638 | 0.107 | 2.90 × 10–9 | no outliers | ||||
cg03995300 | chr17 | 5019989 | ZNF232 | 5’UTR | 0.229 | 0.040 | 1.02 × 10–8 | no outliers |
cgID | Direction of Effect in Discovery Study <10 Years | NTR Replication Study (n = 98) | ALSPAC Replication Study (n = 938) | ||||
---|---|---|---|---|---|---|---|
Estimate | SE | P-Value a | Estimate | SE | P-Value | ||
cg16279140 | − | −0.0326 | 0.0412 | 0.43 | NA | NA | NA |
cg05823759 | + | 0.0329 | 0.0332 | 0.32 | NA | NA | NA |
cg27284194 | + | 0.0668 | 0.0542 | 0.21 | 0.0047 | 0.016 | 0.77 |
cg03995300 | + | −0.0502 | 0.0334 | 0.13 | 0.0140 | 0.011 | 0.19 |
cgID | Chromosome | Position | Gene | Gene Region | ESTIMATE | SE | P-Value |
---|---|---|---|---|---|---|---|
Total Sample (n = 1006) | |||||||
cg16387046 | chr12 | 55248207 | MUCL1 | TSS200 | 0.027 | 0.005 | 4.93 × 10–7 |
Sub-Sample <10 (n = 517) | |||||||
cg11287055 | chr21 | 38630234 | VPS26C (DSCR3) | Body | 0.056 | 0.012 | 4.93 × 10–6 |
cg16704958 | chr21 | 38630728 | VPS26C (DSCR3) | Body | 0.009 | 0.002 | 8.03 × 10–6 |
cg26479305 | chr12 | 52470979 | ATG10 (C12orf44) | 3’UTR | 0.338 | 0.077 | 1.11 × 10–5 |
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Odintsova, V.V.; Hagenbeek, F.A.; Suderman, M.; Caramaschi, D.; van Beijsterveldt, C.E.M.; Kallsen, N.A.; Ehli, E.A.; Davies, G.E.; Sukhikh, G.T.; Fanos, V.; et al. DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood. Nutrients 2019, 11, 2804. https://0-doi-org.brum.beds.ac.uk/10.3390/nu11112804
Odintsova VV, Hagenbeek FA, Suderman M, Caramaschi D, van Beijsterveldt CEM, Kallsen NA, Ehli EA, Davies GE, Sukhikh GT, Fanos V, et al. DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood. Nutrients. 2019; 11(11):2804. https://0-doi-org.brum.beds.ac.uk/10.3390/nu11112804
Chicago/Turabian StyleOdintsova, Veronika V., Fiona A. Hagenbeek, Matthew Suderman, Doretta Caramaschi, Catharina E. M. van Beijsterveldt, Noah A. Kallsen, Erik A. Ehli, Gareth E. Davies, Gennady T. Sukhikh, Vassilios Fanos, and et al. 2019. "DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood" Nutrients 11, no. 11: 2804. https://0-doi-org.brum.beds.ac.uk/10.3390/nu11112804