Height is an important feature of an individual, besides being a risk factor for the future development of non-communicable diseases like diabetes and cardiovascular disorders. Children in low and middle-income countries (LMIC) show more stunting than those in high-income countries (HIC). While as many as 12,000 genetic variants are known to be associated with human height, these variants only correlate with a person’s height around 40% of the time, and that too largely in the HIC such as Europe. Giriraj R Chandak, Chief Scientist, CSIR-Centre for Cellular and Molecular Biology, and his collaborators shed light on what might be happening in other cases, especially in LMICs, in their recent study published in Nature Communications.

This study involved scientists, clinicians, and public health researchers who have been a part of long-term longitudinal studies examining the effect of maternal nutrition on children’s health. They had previously observed positive correlations between the mother’s nutritional status before and during pregnancy on their child’s height and future non-communicable disease risk. DNA methylation, a gene modification in response to various environmental conditions such as nutrition, can either enhance or inhibit the expression of various genes. This control of gene expression by chemical modification of genes is called epigenetic regulation. In this latest study, the group sought to find out if height is controlled epigenetically during childhood.

The scientists collected blood samples of people, categorised them by their age groups, and looked for methylation signatures on 850,000 known sites of DNA methylation, and 650,000 known genetic variants. They checked for independent genetic and epigenetic association with a person’s height. ​“Our study pinpointed to altered methylation in three DNA regions, all of them are known to be a part of the Suppressor of Cytokine Signalling 3 (SOCS3) gene. This gene is known for its role in bone formation and skeletal development in humans. 

And this study shows an inverse relationship between SOCS3 methylation and stunting; more the methylation at this site, lesser are the chances of stunting. Further, DNA methylation at SOCS3 was also associated with height of individuals aged 21 years suggesting a causal role of SOCS3 DNA methylation,” said Chandak. He added, 

We had known that stunting in childhood is associated with onset of many non-communicable diseases and health issues such as increased cardiometabolic risks during adulthood. And we have now systematically shown that height is not only shaped genetically but also by epigenetic factors.

Interestingly, all 12,000 genetic variants were also associated with height in Indians but their effect was significantly lower in this study compared to the European and American counterparts. The study also shows a greater epigenetic influence due to environmental reasons in LMIC children than in HIC children. This underlines the possible early-life interventions that LMICs can particularly develop to alleviate future non-communicable diseases risk. 

“Our analysis suggests that factors operating in early life such as parental socio-economic status and maternal micronutrient status may play a role in deciding children’s heights, and thus, the future health risks. While further work is required to understand the molecular mechanisms, our findings add to the literature highlighting the importance of interventions in early life to improve infant and childhood growth, and metabolic health,” added Kalyanaraman Kumaran, Professor, University of Southampton, a collaborator in the study. The authors of the study hope that such childhood and pre-birth interventions will also help alleviating future health risks in adulthood.

Anura Kurpad, Professor, St John’s Medical College and Research Centre, Bengaluru, an expert in population-wide studies on nutrition and metabolism, and not associated with this study, commented on the significance of its findings. He said, ​“The primary reason for investigating epigenetic modifications in relation to childhood growth is that, unlike genetic variation, these are modifiable by environmental factors such as maternal nutrition, hygiene, etc. This study successfully identified a key epigenetic modifier of height at an early age (5 years), something that was not robustly shown before, and which was well-replicated in multiple cohorts from both LMIC and HICs.”