Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Birth weight is an important factor in newborn and infant survival, and both low and high birth weights are associated with adverse later life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with either maternal or fetal effects on birth weight. Knowledge of the underlying causal genes and pathways is crucial to understand how these loci influence birth weight, and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme upper or lower ends of the normal distribution, and genes implicated in those syndromes may provide valuable information to help prioritise candidate genes at GWAS loci. We examined the proximity of genes implicated in developmental disorders to birth weight GWAS loci at which a fetal effect is either likely or cannot be ruled out. We used simulations to test whether those genes fall disproportionately close to the GWAS loci. We found that birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected by chance. This is the case both when the developmental disorder gene is the nearest gene to the birth weight SNP and also when examining all genes within 258kb of the SNP. This enrichment was driven by genes that cause monogenic developmental disorders with dominant modes of inheritance. We found several examples of SNPs located in the intron of one gene that mark plausible effects via different nearby genes implicated in monogenic short stature, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight loci, which has helped identify GWAS loci likely to have direct fetal effects on birth weight which could not previously be classified as fetal or maternal due to insufficient statistical power.

Effect of Fetal Sex on Total Levels of Maternal Serum Testosterone

The aim of this study was to find out the effect of fetal sex on maternal serum total testosterone level and its application for fetal sex determination.Forty healthy pregnant (second trimester) females were recruited in the study from rural areas of district Dir lower, Khyber Pakhtunkhwa, Pakistan, having complete antenatal record. Twenty of them were carrying single male fetuses and twenty female fetuses. The inclusions criteria were age (25 to 30), second trimester, absence of serious diseases, availability of antenatal record, no drug addiction and no exposure to pesticides. Blood samples at 5 ml size were collected from each woman, serum was obtained and was assayed by Bio-check (USA) kit according to the manufacturer protocol.In male fetus group the mean and SD was 169±27.18 ng/dl and in female fetus group the Mean± SD was 166.6±30.47 ng/dl. There was nosignificant difference (P 0.1062) between the two groups at 95% confidence level.The results suggest that sex of the fetus has no association with maternal serum total testosterone among the study population-and should not be analyzed for sex determination. Further study with bigger sample size of different population groups in different gestational stages is needed to find the fetal effect on maternal serum testosterone because, increased level of testosterone in females can cause aggression, other behavioral changes, acnes and abrupt growth of pubic and axillary hairs.

Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence?

In a previous study, we showed that exposure of rats to dexamethasone (Dex) selectively in late pregnancy produces permanent induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression and hyperglycaemia in the adult offspring. The mechanisms by which glucocorticoids cause this programming are unclear but may involve direct actions on the fetus/neonate, or glucocorticoids may act indirectly by affecting maternal postnatal nursing behaviour. Using a cross-fostering paradigm, the present data demonstrate that switching the offspring at birth from Dex-treated dams to control dams does not prevent induction of PEPCK or hyperglycaemia. Similarly, offspring born to control dams but reared by Dex-treated dams from birth maintain normal glycaemic control. During the neonatal period, injection of saline per se was sufficient to cause exaggeration in adult offspring responses to an oral glucose load, with no additional effect from Dex. However, postnatal treatment with either saline or Dex did not alter hepatic PEPCK activity. Prenatal Dex permanently raised basal plasma corticosterone levels, but under stress conditions there were no differences in circulating corticosterone levels. Likewise, Dex-exposed rats had similar plasma catecholamine concentrations to control animals. These findings show that glucocorticoids programme hyperglycaemia through mechanisms that operate on the fetus or directly on the neonate, rather than via effects that alter maternal postnatal behaviour during the suckling period. The hyperglycaemic response does not appear to result from abnormal sympathoadrenal activity or hypothalamic-pituitary-adrenal response during stress.