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

Issarapu, P.; Arumalla, M.; Elliott, H. R.; Nongmaithem, S. S.; Alagu, S.; Betts, M.; Sajjadi, S.; Kessler, N. J.; Bayyana, S.; Mansuri, S. R.; Derakhshan, M.; V, K. G.; Shrestha, S.; K, K.; Gravio, C. D.; Sahariah, S. A.; Sanderson, E.; Relton, C.; Ward, K. A.; Moore, S. E.; Prentice, A. M.; Lillycrop, K. A.; Fall, C. H. D.; Silver, M. J.; Chandak, G. R.

doi:10.1101/2022.11.30.514849

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bioRxiv · 10.1101/2022.11.30.514849

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

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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 investigated links between blood DNA methylation and child height in four LMIC cohorts (n=1927) and identified a robust association at three CpGs in the suppressor of cytokine signalling 3 (SOCS3) gene which replicated in a high-income country cohort (n=879). SOCS3 methylation (SOCS3m) - height associations were independent of genetic effects. Mendelian randomization analysis confirmed a causal effect of SOCS3m on height. In longitudinal analysis in a LMIC cohort, SOCS3m explained a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increased from birth to 21 years (2% to 18%). Childrens SOCS3m was associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirmed a regulatory effect of SOCS3m on gene expression. Our findings suggest that epigenetic modifications may play an important role in driving child height in LMIC.

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Issarapu, P., Arumalla, M., Elliott, H. R., Nongmaithem, S. S., Alagu, S., Betts, M., Sajjadi, S., Kessler, N. J., Bayyana, S., Mansuri, S. R., Derakhshan, M., V, K. G., Shrestha, S., K, K., Gravio, C. D., Sahariah, S. A., Sanderson, E., Relton, C., Ward, K. A., Moore, S. E., Prentice, A. M., Lillycrop, K. A., Fall, C. H. D., Silver, M. J., Chandak, G. R.. 2022-12-01. DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood. https://doi.org/10.1101/2022.11.30.514849

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