Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide ...association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal ...genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (
= 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.
Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether ...there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.
We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI.
We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association.
Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602).
Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.
Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance with onset or first recognition during pregnancy. Women with a history of GDM are at long-term risk for developing type 2 ...diabetes (T2DM), raising the question to what extent GDM and T2DM share a common genetic architecture. Meta-analysis of candidate gene studies and genome-wide association analysis (GWAS) have identified a number of genes which are reproducibly associated with GDM, including
TCF7L2
,
GCK
,
KCNJ11
,
KCNQ1
,
CDKAL1
,
IGF2BP2
,
MTNR1B
, and
IRS1
. These genes are also associated with T2DM. Candidate gene and GWAS have also identified genes associated with maternal metabolic traits, most of which are also associated with metabolic traits in the general population. Two genes,
BACE2
and
HKDC1
, are uniquely associated with maternal metabolic traits. These studies suggest that there are similarities and differences between the genetic architecture of GDM and T2DM and metabolic quantitative traits in pregnant and non-pregnant populations.
Transversions (Tv's) are more likely to alter the amino acid sequence of proteins than transitions (Ts's), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. ...Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Genetic variants primarily impact gene expression by disrupting the binding of transcription factors (TFs) and other DNA-binding proteins. Because Tv's cause larger changes in the shape of a DNA backbone, we hypothesized that Tv's would have larger impacts on TF binding and gene expression.
Here, we provide multiple lines of evidence demonstrating that Tv's have larger impacts on regulatory DNA including analyses of TF binding motifs and allele-specific TF binding. In these analyses, we observed a depletion of Tv's within TF binding motifs and TF binding sites. Using massively parallel population-scale reporter assays, we also provided empirical evidence that Tv's have larger effects than Ts's on the activity of human gene regulatory elements.
Tv's are more likely to disrupt TF binding, resulting in larger changes in gene expression. Although the observed differences are small, these findings represent a novel, fundamental property of regulatory variation. Understanding the features of functional non-coding variation could be valuable for revealing the genetic underpinnings of complex traits and diseases in future studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity.
Targeted metabolomic assays of clinical ...metabolites, amino acids, and acylcarnitines were performed on fasting and 1-h postglucose serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American mothers (400 from each ancestry group) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and underwent an oral glucose tolerance test at ∼28 weeks gestation.
K-means clustering, which identified patterns of metabolite levels across ancestry groups, demonstrated that, at both fasting and 1-h, levels of the majority of metabolites were similar across ancestry groups. Meta-analyses demonstrated association of a broad array of fasting and 1-h metabolites, including lipids and amino acids and their metabolites, with maternal BMI, glucose levels, and insulin sensitivity before and after adjustment for the different phenotypes. At fasting and 1 h, a mix of metabolites was identified that were common across phenotypes or associated with only one or two phenotypes. Partial correlation estimates, which allowed comparison of the strength of association of different metabolites with maternal phenotypes, demonstrated that metabolites most strongly associated with different phenotypes included some that were common across as well as unique to each phenotype.
Maternal BMI and glycemia have metabolic signatures that are both shared and unique to each phenotype. These signatures largely remain consistent across different ancestry groups and may contribute to the common and independent effects of these two phenotypes on adverse pregnancy outcomes.
Abstract
Context
An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to ...account for potential confounders.
Objective
Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring.
Design and Setting
International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively.
Participants and Main Outcome Measures
In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years.
Results
Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR 95% confidence interval; CI, GDM OR 95% CI; combined OR 95% CI) of childhood overweight/obese BMI (3.00 2.42-3.74, 1.39 1.14-1.71, 3.55 2.49-5.05), obese BMI (3.54 2.70-4.64, 1.73 1.29-2.30, 6.10 4.14-8.99), percent body fat >85th percentile (2.15 1.68-2.75, 1.33 1.03-1.72, 3.88 2.72-5.55), sum of skinfolds >85th percentile (2.35 1.83-3.00, 1.75 1.37-2.24, 3.66 2.55-5.27), and waist circumference >85th percentile (2.52 1.99-3.21, 1.39 1.07-1.80, 4.18 2.93-5.96).
Conclusions
Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity.
We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a ...high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses.
In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2-hour glucose tolerance tests at 28 ...weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous-deleted HKDC1 mouse model (HKDC1+/−) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1+/− mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1+/− mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1+/− mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1+/− mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1+/− mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use.
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