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

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.

High-altitude population neonatal and maternal phenotypes associated with birthweight protection.

BACKGROUND: States which reduce foetal oxygen delivery are associated with impaired intrauterine growth. Hypoxia results when barometric pressure falls with ascent to altitude, and with it the partial pressure of inspired oxygen ('hypobaric hypoxia'). birthweight is reduced when native lowlanders gestate at such high altitude (HA)-an effect mitigated in native (millennia) HA populations. Studying HA populations offer a route to explore the mechanisms by which hypoxia impacts foetal growth. METHODS: Between February 2017 and January 2019, we prospectively studied 316 pregnant women, in Leh, Ladakh (altitude 3524 m, where oxygen partial pressure is reduced by 1/3) and 101 pregnant women living in Delhi (low altitude, 216 m above sea level). RESULTS: Of Ladakhi HA newborns, 14% were small for gestational age (<10th birthweight centile) vs 19% of newborn at low altitude. At HA, increased maternal body mass index, age, and uterine artery (UtA) diameter were positively associated with growth >10th weight centile. CONCLUSIONS: This study showed that Ladakhi offspring birthweight is relatively spared from the expected adverse HA effects. Furthermore, maternal body composition and greater UtA size may be physiological HA adaptations and warrant further study, as they offer potential mechanisms to overcome hypoxia-related growth issues. IMPACT: Reduced foetal oxygen delivery seen in native lowlanders who gestate at HA causes foetal growth restriction-an effect thought to be mitigated in native HA populations. We found that greater maternal body mass and UtA diameter were associated with increased offspring birthweight in a (Ladakh) HA population. This supports a role for them as physiological mediators of adaptation and provides insights into potential mechanisms that may treat hypoxia-related growth issues.

Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India.

There have been concerted efforts toward cataloging rare and deleterious variants in different world populations using high-throughput genotyping and sequencing-based methods. The Indian population is underrepresented or its information with respect to clinically relevant variants is sparse in public data sets. The aim of this study was to estimate the burden of monogenic disease-causing variants in Indian populations. Toward this, we have assessed the frequency profile of monogenic phenotype-associated ClinVar variants. The study utilized a genotype data set (global screening array, Illumina) from 2795 individuals (multiple in-house genomics cohorts) representing diverse ethnic and geographically distinct Indian populations. Of the analyzed variants from Global Screening Array, ~9% were found to be informative and were either not known earlier or underrepresented in public databases in terms of their frequencies. These variants were linked to disorders, namely inborn errors of metabolism, monogenic diabetes, hereditary cancers, and various other hereditary conditions. We have also shown that our study cohort is genetically a better representative of the Indian population than its representation in the 1000 Genome Project (South Asians). We have created a database, ClinIndb, linked to the Leiden Open Variation Database, to help clinicians and researchers in diagnosis, counseling, and development of appropriate genetic screening tools relevant to the Indian populations and Indians living abroad.