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

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

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.

Child, Cytokines, DNA Methylation/genetics, Epigenesis, Genetic, Epigenomics, Female, Humans, Pregnancy, Suppressor of Cytokine Signaling 3 Protein/genetics, Suppressor of Cytokine Signaling Proteins/genetics
2041-1723
Issarapu, Prachand
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Arumalla, Manisha
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Elliott, Hannah R.
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Nongmaithem, Suraj S.
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Sankareswaran, Alagu
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Betts, Modupeh
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Sajjadi, Sara
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Kessler, Noah J.
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Bayyana, Swati
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Mansuri, Sohail R.
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Derakhshan, Maria
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Krishnaveni, G.V.
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Shrestha, Smeeta
a1317ac1-6da8-4f72-8ae0-770f5ab253a3
Kumaran, Kalyanaraman
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Di Gravio, Chiara
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Sahariah, Sirazul A.
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Sanderson, Eleanor
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Relton, Caroline L.
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Ward, Kate A.
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Moore, Sophie E.
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Prentice, Andrew M.
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Lillycrop, Karen A.
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Fall, Caroline H.D.
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Silver, Matt J.
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Chandak, Giriraj R.
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EMPHASIS Study Group
Issarapu, Prachand
f980880e-53a1-477d-affc-7a2f7328504b
Arumalla, Manisha
00fae54e-66e8-4257-877f-59d1c65ce265
Elliott, Hannah R.
5a36681b-c1ba-4d06-8c46-12bc5ebd3bb1
Nongmaithem, Suraj S.
7194b6bd-97e0-481c-bf8d-47f1578cb157
Sankareswaran, Alagu
94d78d8d-233c-4be4-b580-52879792255b
Betts, Modupeh
f1ab0904-e3b7-4d7d-bbcc-9f5edfa65191
Sajjadi, Sara
1604756a-372f-410f-8f35-3f5e28181531
Kessler, Noah J.
2442ea07-46ad-42cd-985b-333d2d917b89
Bayyana, Swati
a910e457-e28c-4557-9519-69ebe981e038
Mansuri, Sohail R.
03714b4a-8541-4d88-915d-c19e122c1f08
Derakhshan, Maria
cda18314-cc31-4397-a2c4-f4258ab24f09
Krishnaveni, G.V.
eb73f522-17b0-4aa9-a7c7-df0014ced8c3
Shrestha, Smeeta
a1317ac1-6da8-4f72-8ae0-770f5ab253a3
Kumaran, Kalyanaraman
de6f872c-7339-4a52-be84-e3bbae707744
Di Gravio, Chiara
4033fc31-5d17-4329-b741-aee8ba31d971
Sahariah, Sirazul A.
00647542-3ca0-44e4-b3bc-f0c84228f7e6
Sanderson, Eleanor
e32217d3-3c2d-46f7-bbc6-eba0d43e1477
Relton, Caroline L.
dcf42a2b-b423-4675-806d-bc581afe17a7
Ward, Kate A.
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Moore, Sophie E.
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Prentice, Andrew M.
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Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Fall, Caroline H.D.
7171a105-34f5-4131-89d7-1aa639893b18
Silver, Matt J.
b80ecb7f-b011-4f37-9b9a-d0c63f1979c4
Chandak, Giriraj R.
d9d4d4ba-6a4b-450d-8889-02e599ca0e1c

Issarapu, Prachand, Arumalla, Manisha, Elliott, Hannah R., Nongmaithem, Suraj S., Sankareswaran, Alagu, Betts, Modupeh, Sajjadi, Sara, Kessler, Noah J., Bayyana, Swati, Mansuri, Sohail R., Derakhshan, Maria, Krishnaveni, G.V., Shrestha, Smeeta, Kumaran, Kalyanaraman, Di Gravio, Chiara, Sahariah, Sirazul A., Sanderson, Eleanor, Relton, Caroline L., Ward, Kate A., Moore, Sophie E., Prentice, Andrew M., Lillycrop, Karen A., Fall, Caroline H.D., Silver, Matt J. and Chandak, Giriraj R. , EMPHASIS Study Group (2023) DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood. Nature Communications, 14 (1), [5200]. (doi:10.1038/s41467-023-40607-0).

Record type: Article

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.

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Accepted/In Press date: 1 August 2023
e-pub ahead of print date: 25 August 2023
Published date: 25 August 2023
Additional Information: Funding Information: MMNP: We are grateful to the families who took part, and the team of fieldworkers, nurses, research assistants, and data managers who carried out the study. The original trial was supported by the Wellcome Trust, United Kingdom; the Medical Research Council, United Kingdom; the Department for International Development, United Kingdom; USAID; the Parthenon Trust, Switzerland; and the Industrial Credit and Investment Corporation of India Bank Ltd Social Initiatives Group, Mumbai, India. The SARAS KIDS children’s follow-up study was funded by the Medical Research Council, UK research grant no: MR/M005186/1. PMMST and ENID: We thank all the study participants in West Kiang, The Gambia for their time and commitment. We also thank members of the laboratory and field teams. We acknowledge the work of Z. Herceg, M.N. Routledge, Y.Y. Gong, and H. Hernandez-Vargas in acquiring the ENID 2-year 450k array data and Toby Candler in acquiring samples and data in the follow-up study in 5–7-year-old children. PMMST was supported by MRC (U1232661351, U105960371, and MC-A760-5QX00) and DFID under the MRC/DFID Concordat, and other members of the Gambian team were supported by MRC grants U105960371, U123261351 and MR/M01424X/1. The ENID trial was jointly funded by the UK Medical Research Council (MRC) and the Department for International Development (DFID) under the MRC/DFID Concordat agreement (MRC Program MC-A760-5QX00). Methylation analysis of ENID early childhood samples was supported by the Bill & Melinda Gates Foundation (grant no. OPP1 066947). The generation of methylation data from the same cohort in late childhood was funded by the UK MRC (grant no. MC_PC_MR/RO20183/1). The EMPHASIS study was jointly funded by MRC, DFID, and the Department of Biotechnology (DBT), Ministry of Science and Technology, India, under the Newton Fund initiative (MRC Grant No.: MR/ N006208/1 and DBT Grant No.: BT/IN/DBT-MRC/DFID/24/GRC/2015–16). MPC: We thank all the participating families, CSI Holdsworth Memorial Hospital staff, the research team, and the staff of the MRC Lifecourse Epidemiology Unit for their support. MPC was supported by the Parthenon Trust, Switzerland; the Wellcome Trust, UK; the MRC, UK and the Department for International Development (UK). The follow-up at 21 years was supported by the DBT/Wellcome Trust India Alliance Fellowship [Grant Number: IA/CPHS/16/1/502655]. Thanks to the Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, India for funds for generating high-throughput genomic and methylation data. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Hannah R. Elliott, Eleanor C.M. Sanderson, and Caroline L. Relton are members of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/5 and MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Funding Information: MMNP: We are grateful to the families who took part, and the team of fieldworkers, nurses, research assistants, and data managers who carried out the study. The original trial was supported by the Wellcome Trust, United Kingdom; the Medical Research Council, United Kingdom; the Department for International Development, United Kingdom; USAID; the Parthenon Trust, Switzerland; and the Industrial Credit and Investment Corporation of India Bank Ltd Social Initiatives Group, Mumbai, India. The SARAS KIDS children’s follow-up study was funded by the Medical Research Council, UK research grant no: MR/M005186/1. PMMST and ENID: We thank all the study participants in West Kiang, The Gambia for their time and commitment. We also thank members of the laboratory and field teams. We acknowledge the work of Z. Herceg, M.N. Routledge, Y.Y. Gong, and H. Hernandez-Vargas in acquiring the ENID 2-year 450k array data and Toby Candler in acquiring samples and data in the follow-up study in 5–7-year-old children. PMMST was supported by MRC (U1232661351, U105960371, and MC-A760-5QX00) and DFID under the MRC/DFID Concordat, and other members of the Gambian team were supported by MRC grants U105960371, U123261351 and MR/M01424X/1. The ENID trial was jointly funded by the UK Medical Research Council (MRC) and the Department for International Development (DFID) under the MRC/DFID Concordat agreement (MRC Program MC-A760-5QX00). Methylation analysis of ENID early childhood samples was supported by the Bill & Melinda Gates Foundation (grant no. OPP1 066947). The generation of methylation data from the same cohort in late childhood was funded by the UK MRC (grant no. MC_PC_MR/RO20183/1). The EMPHASIS study was jointly funded by MRC, DFID, and the Department of Biotechnology (DBT), Ministry of Science and Technology, India, under the Newton Fund initiative (MRC Grant No.: MR/ N006208/1 and DBT Grant No.: BT/IN/DBT-MRC/DFID/24/GRC/2015–16). MPC: We thank all the participating families, CSI Holdsworth Memorial Hospital staff, the research team, and the staff of the MRC Lifecourse Epidemiology Unit for their support. MPC was supported by the Parthenon Trust, Switzerland; the Wellcome Trust, UK; the MRC, UK and the Department for International Development (UK). The follow-up at 21 years was supported by the DBT/Wellcome Trust India Alliance Fellowship [Grant Number: IA/CPHS/16/1/502655]. Thanks to the Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, India for funds for generating high-throughput genomic and methylation data. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Hannah R. Elliott, Eleanor C.M. Sanderson, and Caroline L. Relton are members of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/5 and MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Publisher Copyright: © 2023, Springer Nature Limited.
Keywords: Child, Cytokines, DNA Methylation/genetics, Epigenesis, Genetic, Epigenomics, Female, Humans, Pregnancy, Suppressor of Cytokine Signaling 3 Protein/genetics, Suppressor of Cytokine Signaling Proteins/genetics

Identifiers

Local EPrints ID: 481787
URI: http://eprints.soton.ac.uk/id/eprint/481787
ISSN: 2041-1723
PURE UUID: 304794cc-7457-44f4-8a28-671e97a21086
ORCID for Kate A. Ward: ORCID iD orcid.org/0000-0001-7034-6750
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489
ORCID for Caroline H.D. Fall: ORCID iD orcid.org/0000-0003-4402-5552

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Date deposited: 07 Sep 2023 16:42
Last modified: 18 Mar 2024 03:34

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Contributors

Author: Prachand Issarapu
Author: Manisha Arumalla
Author: Hannah R. Elliott
Author: Suraj S. Nongmaithem
Author: Alagu Sankareswaran
Author: Modupeh Betts
Author: Sara Sajjadi
Author: Noah J. Kessler
Author: Swati Bayyana
Author: Sohail R. Mansuri
Author: Maria Derakhshan
Author: G.V. Krishnaveni
Author: Smeeta Shrestha
Author: Chiara Di Gravio
Author: Sirazul A. Sahariah
Author: Eleanor Sanderson
Author: Caroline L. Relton
Author: Kate A. Ward ORCID iD
Author: Sophie E. Moore
Author: Andrew M. Prentice
Author: Matt J. Silver
Author: Giriraj R. Chandak
Corporate Author: EMPHASIS Study Group

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