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

How Local Factors Affect The Exponents Of Forced Polymer Translocation Through A Nano-Pore

We study polymer translocation through a narrow pore driven by a bias present inside the pore with an aim to compare predictions of the existing theoretical results with those that we obtain using Langevin dynamics simulation in three dimensions(3D). We find that the translocation exponent α (〈 τ 〉 ∼ Nα) decreases from 1.35 to 1.2 as the width of the pore is decreased from 1.5 σ to 1.1 σ. The exponent א = 1.2 (extracted from chain lengths up to N = 256) not only violates the lower limit 1 + ν proposed by Kantor and Kardar (Y. Kantor and M. Kardar, Phys. Rev. E, 69, 021806 (2004)) earlier but also lower than the more recently proposed lower limit (1 + 2 ν) / (1 + ν) by Vocks et al. (H. Vocks, D. Panja, G. T. Barkema, and R. C. Ball, J. Phys.: Condens. Matter 20, 095224 (2008)). We find that the average 〈 over(R, ̄)g 〉 calculated during the entire translocation process is dominated by the equilibrium configurations at the cis side and therefore, relatively insensitive to the pore width and approximately described by the equilibrium Flory exponent ν. The velocity of the center of mass of the translocating chain on the contrary exhibits a systematic variation. Therefore, if we assume (〈 τ 〉 ∼ 〈 over(R, ̄)g 〉 / 〈 vC M 〉), the dependence of 〈 vC M 〉 on the pore width appears to be the primary factor that affects the translocation exponent. © 2010

How local factors affect the exponents of forced polymer translocation through a nano-pore

AbstractWe study polymer translocation through a narrow pore driven by a bias present inside the pore with an aim to compare predictions of the existing theoretical results with those that we obtain using Langevin dynamics simulation in three dimensions(3D). We find that the translocation exponent α(〈τ〉∼Nα) decreases from 1.35 to 1.2 as the width of the pore is decreased from 1.5σ to 1.1σ. The exponent ℵ=1.2 (extracted from chain lengths up to N=256) not only violates the lower limit 1+ν proposed by Kantor and Kardar (Y. Kantor and M. Kardar, Phys. Rev. E, 69, 021806 (2004)) earlier but also lower than the more recently proposed lower limit (1+2ν)/(1+ν) by Vocks et al. (H. Vocks, D. Panja, G. T. Barkema, and R. C. Ball, J. Phys.: Condens. Matter 20, 095224 (2008)). We find that the average 〈R̄g〉 calculated during the entire translocation process is dominated by the equilibrium configurations at the cis side and therefore, relatively insensitive to the pore width and approximately described by the equilibrium Flory exponent ν. The velocity of the center of mass of the translocating chain on the contrary exhibits a systematic variation. Therefore, if we assume (〈τ〉∼〈R̄g〉/〈vCM〉), the dependence of 〈vCM〉 on the pore width appears to be the primary factor that affects the translocation exponent

Fetal gene variants associated with birth weight protection in a native high altitude Ladakhi population

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.</p

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 hypoxic 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-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.</div

Fetal gene variants associated with birth weight protection in a native high altitude Ladakhi population

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.</p

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 hypoxic 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-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.</div

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.</p

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.</p

Manhattan plot showing GWAS results of birth weight genes across chromosomes.

(TIF)</p