Population history and genome wide association studies of birth weight in a native high altitude Ladakhi population

Abstract

Pathological low birth weight due to fetal growth restriction (FGR) is an important predictor of adverse obstetric and neonatal outcomes. 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 permits exploration of the role of hypoxia in FGR pathogenesis, and perhaps of FGR pathogenesis more broadly. We studied the umbilical cord blood DNA of 316 neonates born to pregnant women managed at the Sonam Norboo Memorial Hospital, Ladakh (altitude 3540m) between February 2017 and January 2019. Principal component, admixture and genome wide association studies (GWAS) were applied to dense single nucleotide polymorphism (SNP) genetic data, to explore ancestry and genetic predictors of 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. Although no variants achieved genome wide significance, we observed nominal association of seven variants across genes (ZBTB38, ZFP36L2, HMGA2, CDKAL1, PLCG1) previously associated with birthweight.

Altitude Modifies the Effect of Parity on Birth Weight/Length Ratio: A Study Comprising 2,057,702 Newborns between 1984 and 2020 in Austria

“…Both factors play major roles in the placentation process and the maintenance of the placental function, which consists primarily of the oxygenation and nutrition of the fetus [ 19 , 26 ]. Other authors also suggest genetic or epigenetic influences operating the effect of altitude on fetal growth [ 18 , 27 ].…”

Genetic architecture and adaptation of Ladakh highlanders of trans-Himalayas

“…The abundance and diversity of mitochondrial haplogroup M9 highlight the potential genetic contribution of the Tibetan Plateau and China 30 . This genetic proximity to East Asians is also supported by the frequency of Hg A, a haplogroup not so common in India but very common among Tibeto-Burmans, including Tibetans and Mongolians [28][29][30][31][32] . Genetic studies carried out to date are based on a limited number of samples and low-resolution markers.…”