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

EMPHASIS study group

doi:10.1101/2022.11.30.514849

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

EMPHASIS study group

Research output: Contribution to journal › Article (Academic Journal) › peer-review

5 Citations (Scopus)

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
DOIs	https://doi.org/10.1101/2022.11.30.514849 https://doi.org/10.1038/s41467-023-40607-0
Publication status	Published - 25 Aug 2023

Bibliographical note

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.

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© 2023, Springer Nature Limited.

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Keywords

Female
Pregnancy
Humans
Child
DNA Methylation/genetics
Suppressor of Cytokine Signaling Proteins/genetics
Epigenesis, Genetic
Epigenomics
Cytokines
Suppressor of Cytokine Signaling 3 Protein/genetics

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@article{51fcfa93245a4da7a7fbd8a8065864a0,

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.",

keywords = "Female, Pregnancy, Humans, Child, DNA Methylation/genetics, Suppressor of Cytokine Signaling Proteins/genetics, Epigenesis, Genetic, Epigenomics, Cytokines, Suppressor of Cytokine Signaling 3 Protein/genetics",

author = "\{EMPHASIS study group\} and 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\}",

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

year = "2023",

month = aug,

day = "25",

doi = "10.1101/2022.11.30.514849",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

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

AU - EMPHASIS study group

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

N1 - 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.

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.

KW - Female

KW - Pregnancy

KW - Humans

KW - Child

KW - DNA Methylation/genetics

KW - Suppressor of Cytokine Signaling Proteins/genetics

KW - Epigenesis, Genetic

KW - Epigenomics

KW - Cytokines

KW - Suppressor of Cytokine Signaling 3 Protein/genetics

U2 - 10.1101/2022.11.30.514849

DO - 10.1101/2022.11.30.514849

M3 - Article (Academic Journal)

C2 - 37626025

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 5200

ER -

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

Abstract

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