Pathological low birth weight ‘fetal growth restriction’ (FGR) is an important predictor of adverse obstetric outcomes including stillbirth. It is more common amongst native lowlanders when gestating in the hypoxic environment of high altitude, whilst populations who have resided at high altitude for many generations are relatively protected. Genetic study of pregnant populations at high altitude allows for exploration of the hypoxic influence on FGR pathogenesis.Pregnant women were recruited from Sonam Norboo Memorial Hospital, Ladakh between February 2017- January 2019 in this study. Principal component, admixture and genome wide association analysis (GWAS) were applied on umbilical cord blood DNA samples from 316 neonates, to explore ancestry and the genetic influence on low birth weight.Our findings support Tibetan ancestry in the Ladakhi population, with subsequent admixture with neighboring Indo-Aryan populations. Fetal growth protection was evident in Ladakhi neonates. Seven loci from five different genomic regions (ZBTB38, ZFP36L2, HMGA2, CDKAL1, PLCG1) previously associated with birthweight, were likewise similarly associated here. In summary, the Ladakhi population show evidence of enrichment of variants in genes that may help mitigate altitude-associated fetal growth restriction, supporting novel biological pathways and therapeutic targets for FGR, worthy of further investigation.
