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

Abstract

AbstractHuman 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).SOCS3methylation (SOCS3m) – height associations were independent of genetic effects. Mendelian randomization analysis confirmed a causal effect ofSOCS3mon height. In longitudinal analysis in a LMIC cohort,SOCS3mexplained 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%). Children’sSOCS3mwas associated with prenatal maternal folate and socio-economic status.In-vitrocharacterization confirmed a regulatory effect ofSOCS3mon gene expression. Our findings suggest that epigenetic modifications may play an important role in driving child height in LMIC.