DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

Prachand Issarapu, Manisha Arumalla, Hannah R. Elliott, Suraj S. Nongmaithem, Alagu Sankareswaran, Modupeh Betts, Sara Sajjadi, Noah J. Kessler, Swati Bayyana, Sohail R. Mansuri, Maria Derakhshan, G. V. Krishnaveni, Smeeta Shrestha, Kalyanaraman Kumaran, Chiara Gravio, Sirazul A. Sahariah, Eleanor Sanderson, Caroline L. Relton, Kate A. Ward, Sophie E. Moore, Andrew M. Prentice, Karen A. Lillycrop, Caroline H. D. Fall, Matt J. Silver () and Giriraj R. Chandak ()
Additional contact information
Prachand Issarapu: CSIR-Centre for Cellular and Molecular Biology
Manisha Arumalla: CSIR-Centre for Cellular and Molecular Biology
Hannah R. Elliott: MRC Integrative Epidemiology Unit at the University of Bristol
Suraj S. Nongmaithem: CSIR-Centre for Cellular and Molecular Biology
Alagu Sankareswaran: CSIR-Centre for Cellular and Molecular Biology
Modupeh Betts: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
Sara Sajjadi: CSIR-Centre for Cellular and Molecular Biology
Noah J. Kessler: University of Cambridge
Swati Bayyana: CSIR-Centre for Cellular and Molecular Biology
Sohail R. Mansuri: CSIR-Centre for Cellular and Molecular Biology
Maria Derakhshan: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
G. V. Krishnaveni: CSI Holdsworth Memorial Hospital
Smeeta Shrestha: CSIR-Centre for Cellular and Molecular Biology
Kalyanaraman Kumaran: CSI Holdsworth Memorial Hospital
Chiara Gravio: Vanderbilt University Medical Center
Sirazul A. Sahariah: Centre for the Study of Social Change
Eleanor Sanderson: MRC Integrative Epidemiology Unit at the University of Bristol
Caroline L. Relton: MRC Integrative Epidemiology Unit at the University of Bristol
Kate A. Ward: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
Sophie E. Moore: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
Andrew M. Prentice: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
Karen A. Lillycrop: University of Southampton
Caroline H. D. Fall: University of Southampton
Matt J. Silver: MRC Unit The Gambia at The London School of Hygiene and Tropical Medicine (LSHTM)
Giriraj R. Chandak: CSIR-Centre for Cellular and Molecular Biology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigate links between blood DNA methylation and child height in four LMIC cohorts (n = 1927) and identify a robust association at three CpGs in the suppressor of cytokine signaling 3 (SOCS3) gene which replicates in a high-income country cohort (n = 879). SOCS3 methylation (SOCS3m)—height associations are independent of genetic effects. Mendelian randomization analysis confirms a causal effect of SOCS3m on height. In longitudinal analysis, SOCS3m explains a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increases from birth to 21 years. Children’s SOCS3m is associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirms a regulatory effect of SOCS3m on gene expression. Our findings suggest epigenetic modifications may play an important role in driving child height in LMIC.

Date: 2023
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DOI: 10.1038/s41467-023-40607-0

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