Babies of South Asian and European Ancestry Show Similar Associations with Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns

Size at birth is known to be influenced by various fetal and maternal factors including genetic effects. South Asians have a high burden of low birthweight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic score (fGS) and maternal genetic score (mGS) from 196 birthweight-associated variants identified in Europeans and conducted association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6 years’ intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from above cohorts were compared with South Asians in UK BioBank and The Exeter Family Study of Childhood Health, a European ancestry cohort. Birthweight increased by 50.7g and 33.6g per standard deviation of fGS (p = 9.1x10^-11) and mGS (p = 0.003) respectively in South Asians. A relatively weaker maternal genetic score effect compared to Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birthweight was strongly associated with body size in both childhood and adolescence (p = 3x10^-5 - 1.9x10^-51), however, fetal genetic score was associated with body size in childhood only (p < 0.01) and with head circumference, fasting glucose and triglycerides in adults (p < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birthweight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.