The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

doi:10.1073/pnas.1820843116

. 2020 Sep 22;117(38):23329-23335.

doi: 10.1073/pnas.1820843116. Epub 2019 Oct 14.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

Lisa M McEwen¹, Kieran J O'Donnell^{2

3}, Megan G McGill², Rachel D Edgar¹, Meaghan J Jones¹, Julia L MacIsaac¹, David Tse Shen Lin¹, Katia Ramadori¹, Alexander Morin¹, Nicole Gladish¹, Elika Garg², Eva Unternaehrer², Irina Pokhvisneva², Neerja Karnani^{4

5}, Michelle Z L Kee⁴, Torsten Klengel⁶, Nancy E Adler^{3

7

8}, Ronald G Barr^{3

9}, Nicole Letourneau^{10

11}, Gerald F Giesbrecht^{10

12}, James N Reynolds¹³, Darina Czamara¹⁴, Jeffrey M Armstrong¹⁵, Marilyn J Essex¹⁵, Carolina de Weerth¹⁶, Roseriet Beijers¹⁷, Marieke S Tollenaar¹⁸, Bekh Bradley¹⁹, Tanja Jovanovic¹⁹, Kerry J Ressler⁶, Meir Steiner²⁰, Sonja Entringer^{21

22}, Pathik D Wadhwa^{22

23

24

25}, Claudia Buss²¹, Nicole R Bush⁷, Elisabeth B Binder^{3

14

19}, W Thomas Boyce^{3

7

8}, Michael J Meaney^{2

3

4

26}, Steve Horvath^{27

28}, Michael S Kobor^{29

3}

Affiliations

¹ Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada V5Z 4H4.
² Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada H4H 1R3.
³ Child and Brain Development Program, Canadian Institute for Advanced Research (CIFAR) Institute, Toronto, ON, Canada M5G 1M1.
⁴ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR); Singapore 117609.
⁵ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596.
⁶ Department of Psychiatry, Harvard Medical School-McLean Hospital, Belmont, MA 02478.
⁷ Department of Psychiatry, University of California, San Francisco, CA 94143.
⁸ Department of Pediatrics, University of California, San Francisco, CA 94143.
⁹ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
¹⁰ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada T2N 4N1.
¹¹ Faculty of Nursing, University of Calgary, Calgary, AB, Canada T2N 1N4.
¹² Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 1N4.
¹³ Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
¹⁴ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
¹⁵ Department of Psychiatry, University of Wisconsin-Madison, Madison, WI 53706.
¹⁶ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR, Nijmegen, The Netherlands.
¹⁷ Behavioural Science Institute, Radboud University, 6525 HR, Nijmegen, The Netherlands.
¹⁸ Leiden Institute for Brain and Cognition, Institute of Psychology, Leiden University, 2300 RB, Leiden, The Netherlands.
¹⁹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322.
²⁰ Department of Psychiatry and Behavioural Neurosciences, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada L8S 4L8.
²¹ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, 10117 Berlin, Germany.
²² Development, Health, and Disease Research Program, University of California, Irvine, CA 92617.
²³ Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, 92617.
²⁴ Department of Obstetrics and Gynecology, School of Medicine, University of California, Irvine, CA, 92617.
²⁵ Department of Epidemiology, School of Medicine, University of California, Irvine, CA, 92617.
²⁶ Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596.
²⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; shorvath@mednet.ucla.edu msk@bcchr.ca.
²⁸ Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA 90095.
²⁹ Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada V5Z 4H4; shorvath@mednet.ucla.edu msk@bcchr.ca.

PMID: 31611402
PMCID: PMC7519312
DOI: 10.1073/pnas.1820843116

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

Lisa M McEwen et al. Proc Natl Acad Sci U S A. 2020.

. 2020 Sep 22;117(38):23329-23335.

doi: 10.1073/pnas.1820843116. Epub 2019 Oct 14.

Authors

Affiliations

¹ Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada V5Z 4H4.
² Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada H4H 1R3.
³ Child and Brain Development Program, Canadian Institute for Advanced Research (CIFAR) Institute, Toronto, ON, Canada M5G 1M1.
⁴ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR); Singapore 117609.
⁵ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596.
⁶ Department of Psychiatry, Harvard Medical School-McLean Hospital, Belmont, MA 02478.
⁷ Department of Psychiatry, University of California, San Francisco, CA 94143.
⁸ Department of Pediatrics, University of California, San Francisco, CA 94143.
⁹ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
¹⁰ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada T2N 4N1.
¹¹ Faculty of Nursing, University of Calgary, Calgary, AB, Canada T2N 1N4.
¹² Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 1N4.
¹³ Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
¹⁴ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
¹⁵ Department of Psychiatry, University of Wisconsin-Madison, Madison, WI 53706.
¹⁶ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR, Nijmegen, The Netherlands.
¹⁷ Behavioural Science Institute, Radboud University, 6525 HR, Nijmegen, The Netherlands.
¹⁸ Leiden Institute for Brain and Cognition, Institute of Psychology, Leiden University, 2300 RB, Leiden, The Netherlands.
¹⁹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322.
²⁰ Department of Psychiatry and Behavioural Neurosciences, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada L8S 4L8.
²¹ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, 10117 Berlin, Germany.
²² Development, Health, and Disease Research Program, University of California, Irvine, CA 92617.
²³ Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, 92617.
²⁴ Department of Obstetrics and Gynecology, School of Medicine, University of California, Irvine, CA, 92617.
²⁵ Department of Epidemiology, School of Medicine, University of California, Irvine, CA, 92617.
²⁶ Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596.
²⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; shorvath@mednet.ucla.edu msk@bcchr.ca.
²⁸ Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA 90095.
²⁹ Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada V5Z 4H4; shorvath@mednet.ucla.edu msk@bcchr.ca.

PMID: 31611402
PMCID: PMC7519312
DOI: 10.1073/pnas.1820843116

Abstract

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Keywords: DNA methylation; adolescence; age; development; epigenetic clock.

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Conflict of interest statement

The authors declare no competing interest.

Figures

**Fig. 1.**
Pediatric buccal DNA methylation age accurately predicted chronological age. (A) The training data (datasets 1 through 7) was used in an elastic net regression for selection of 94 age-related CpG sites. Estimated age (PedBE age) (y axis) versus chronological age (x axis). (B) The test data (datasets 8 through 11) was to independently assess the PedBE clock (r = 0.98, test error = 0.35 y). Each data point represents an individual, with the color indicating the corresponding dataset. Solid black and dashed lines denote the linear regression and perfect correlation lines, respectively.

**Fig. 2.**
Longitudinal data demonstrated higher accuracy of the PedBE clock as compared to the pan-tissue Horvath DNAm clock. (A, *Left*) Dataset 10 PedBE clock versus chronological age across 2 time points (follow-up ranged from 6 mo to 2 y, depending on the individual). Each point color represents an individual separated by a line indicating the time between sampling. (*Right*) Dataset 10 pan-tissue Horvath DNAm clock versus chronological age. (B, *Left*) Dataset 11 PedBE clock versus age across 2 times points separated by 1 y between sampling. (*Right*) Dataset 11 pan-tissue Horvath DNAm clock versus chronological age. Each colored line represents an individual and the time between sampling is denoted by the beginning and end of each line. Time gaps between sample collection varied across individuals ranging from 6 mo to 2 y. Additionally, for dataset 10, individuals at time point one varied in age between 4 and 12 y. PedBE age was calculated for each individual at both time points.

**Fig. 3.**
PedBE deviation was associated with gestational age at 3 and 9 mo and individuals diagnosed with ASD in independent cohorts. (A) Dataset 16 is a longitudinal cohort with sampling at 3 mo (*Left*) and 9 mo (*Right*) of age in the same individuals. (B) In dataset 9B (n = 81), PedBE age deviation equals PedBE regressed onto chronological age, while controlling for sex, batch, predicted buccal proportion, and ethnicity. A nonparametric propensity score-matching method was applied to ensure the groups were balanced regarding covariate measures.

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References

1. Horvath S., DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). - PMC - PubMed
1. Horvath S., Raj K., DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 23, 223 (2018). - PubMed
1. Simpkin A. J., et al. , Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies. Hum. Mol. Genet. 25, 191–201 (2016). - PMC - PubMed
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[1] Horvath S., DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). - PMC - PubMed

[2] Horvath S., DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). - PMC - PubMed

[3] Horvath S., Raj K., DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 23, 223 (2018). - PubMed

[4] Horvath S., Raj K., DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 23, 223 (2018). - PubMed

[5] Simpkin A. J., et al. , Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies. Hum. Mol. Genet. 25, 191–201 (2016). - PMC - PubMed

[6] Simpkin A. J., et al. , Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies. Hum. Mol. Genet. 25, 191–201 (2016). - PMC - PubMed

[7] Goldman J., Becker M. L., Jones B., Clements M., Leeder J. S., Development of biomarkers to optimize pediatric patient management: What makes children different? Biomark Med 5, 781–794 (2011) - PMC - PubMed

[8] Goldman J., Becker M. L., Jones B., Clements M., Leeder J. S., Development of biomarkers to optimize pediatric patient management: What makes children different? Biomark Med 5, 781–794 (2011) - PMC - PubMed

[9] Alisch R. S., et al. , Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623–632 (2012). - PMC - PubMed

[10] Alisch R. S., et al. , Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623–632 (2012). - PMC - PubMed

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The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

Affiliations

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

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Conflict of interest statement

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