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.

Fig 1. Principal Component Analysis (PCA) of Ladakhi population.

PCA of Ladakhi and its neighboring populations are indicated in the figure legend. First and second components of PCA analysis with individual clusters labelled by different colours.

Fig 2. ADMIXTURE analysis of the Ladakhi population.

ADMIXTURE analysis for K = 2 (top), K = 3 (middle) and K = 4 (bottom). ADMIXTURE analysis shows Ladakhi contain higher number of Tibeto-Burman ancestries and are relatively closer to Tibetans.

Fig 3. Evidence of admixture in Ladakhi between lowland or Indo-Aryan populations and highland or north/east Asian populations measured using f3 outgroup statistics.

Along the x axis is the f3 statistic score. The more negative that statistic is, the greater is evidence of admixture. The error bars correspond to three standard errors of the estimated f3 statistic. Along the y axis are different pairs of putative source populations for an admixture event which creates the modern Ladakhi population.