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 Di 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; Giriraj R. Chandak; Chiara Di Gravio; Ramesh D. Potdar; Harsha Chopra; Harshad Sane; Meera Gandhi; Landing Jarjou; Ann Prentice; Sarah H. Kehoe; Stephen Owens

doi:10.1038/s41467-023-40607-0

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 Di Gravio, Sirazul A. Sahariah, Eleanor Sanderson, Caroline L. Relton, Kate A. Ward, Sophie E. MooreAndrew M. Prentice, Karen A. Lillycrop, Caroline H.D. Fall, Matt J. Silver, Giriraj R. Chandak, Chiara Di Gravio, Ramesh D. Potdar, Harsha Chopra, Harshad Sane, Meera Gandhi, Landing Jarjou, Ann Prentice, Sarah H. Kehoe, Stephen Owens

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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.

Original language	English
Article number	5200
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40607-0
Publication status	Published - 25 Aug 2023

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© 2023, Springer Nature Limited.

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Issarapu, P., Arumalla, M., Elliott, H. R., Nongmaithem, S. S., Sankareswaran, A., Betts, M., Sajjadi, S., Kessler, N. J., Bayyana, S., Mansuri, S. R., Derakhshan, M., Krishnaveni, G. V., Shrestha, S., Kumaran, K., Di Gravio, C., Sahariah, S. A., Sanderson, E., Relton, C. L., Ward, K. A., ... Owens, S. (2023). DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood. Nature Communications, 14(1), Article 5200. https://doi.org/10.1038/s41467-023-40607-0

@article{b6842c1678fa439da4ca231b02f4263b,

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

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{\textquoteright}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.",

author = "Prachand Issarapu and Manisha Arumalla and Elliott, {Hannah R.} and Nongmaithem, {Suraj S.} and Alagu Sankareswaran and Modupeh Betts and Sara Sajjadi and Kessler, {Noah J.} and Swati Bayyana and Mansuri, {Sohail R.} and Maria Derakhshan and Krishnaveni, {G. V.} and Smeeta Shrestha and Kalyanaraman Kumaran and {Di Gravio}, Chiara and Sahariah, {Sirazul A.} and Eleanor Sanderson and Relton, {Caroline L.} and Ward, {Kate A.} and Moore, {Sophie E.} and Prentice, {Andrew M.} and Lillycrop, {Karen A.} and Fall, {Caroline H.D.} and Silver, {Matt J.} and Chandak, {Giriraj R.} and {Di Gravio}, Chiara and Potdar, {Ramesh D.} and Harsha Chopra and Harshad Sane and Meera Gandhi and Landing Jarjou and Ann Prentice and Kehoe, {Sarah H.} and Stephen Owens",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = aug,

day = "25",

doi = "10.1038/s41467-023-40607-0",

language = "English",

volume = "14",

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Issarapu, P, Arumalla, M, Elliott, HR, Nongmaithem, SS, Sankareswaran, A, Betts, M, Sajjadi, S, Kessler, NJ, Bayyana, S, Mansuri, SR, Derakhshan, M, Krishnaveni, GV, Shrestha, S, Kumaran, K, Di Gravio, C, Sahariah, SA, Sanderson, E, Relton, CL, Ward, KA, Moore, SE, Prentice, AM, Lillycrop, KA, Fall, CHD, Silver, MJ, Chandak, GR, Di Gravio, C, Potdar, RD, Chopra, H, Sane, H, Gandhi, M, Jarjou, L, Prentice, A, Kehoe, SH & Owens, S 2023, 'DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood', Nature Communications, vol. 14, no. 1, 5200. https://doi.org/10.1038/s41467-023-40607-0

TY - JOUR

T1 - DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

AU - Issarapu, Prachand

AU - Arumalla, Manisha

AU - Elliott, Hannah R.

AU - Nongmaithem, Suraj S.

AU - Sankareswaran, Alagu

AU - Betts, Modupeh

AU - Sajjadi, Sara

AU - Kessler, Noah J.

AU - Bayyana, Swati

AU - Mansuri, Sohail R.

AU - Derakhshan, Maria

AU - Krishnaveni, G. V.

AU - Shrestha, Smeeta

AU - Kumaran, Kalyanaraman

AU - Di Gravio, Chiara

AU - Sahariah, Sirazul A.

AU - Sanderson, Eleanor

AU - Relton, Caroline L.

AU - Ward, Kate A.

AU - Moore, Sophie E.

AU - Prentice, Andrew M.

AU - Lillycrop, Karen A.

AU - Fall, Caroline H.D.

AU - Silver, Matt J.

AU - Chandak, Giriraj R.

AU - Di Gravio, Chiara

AU - Potdar, Ramesh D.

AU - Chopra, Harsha

AU - Sane, Harshad

AU - Gandhi, Meera

AU - Jarjou, Landing

AU - Prentice, Ann

AU - Kehoe, Sarah H.

AU - Owens, Stephen

PY - 2023/8/25

Y1 - 2023/8/25

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-023-40607-0

DO - 10.1038/s41467-023-40607-0

M3 - Article

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AN - SCOPUS:85168732457

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5200

ER -

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

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