Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype-phenotype correlations accurately. The aim of this study was to identify type 2 ...diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems.
An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions.
The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D.
By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS.
An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions.
Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive.
This study aims to explore the associations of maternal and umbilical cord ...serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes.
We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography-tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system.
Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all
< .001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999;
= .032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes.
Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies.
Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational ...diabetes mellitus (GDM) is distinct from that underlying T2D. In this study of >5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced β-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. The effect size for this cluster's association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.
The present research reviews the most recent ten years, 2010–2019, of the work published in The Leadership Quarterly (LQ). We follow on prior decade-focused reviews published in LQ, including the ...period 1990–1999 (Lowe & Gardner, 2000) and 2000–2009 (Gardner, Lowe, Cogliser, Moss & Mahoney, 2010). The present work complements and expands the first two reviews by documenting how the field has evolved with new characters, methodologies, and theories emerging while others decline and become less relevant. We extend the story of how LQ emerged from a start-up niche journal, evolved into the predominant outlet for leadership research and new theories, gained awareness of a growing need to reduce construct proliferation, and adopted increasingly sophisticated methodological techniques that call into question some of the field's prior research findings.
Abstract
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal ...genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including ...glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.
This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.
Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (β=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.
Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a reprise of Lowe and Gardner's (2000) review of
The Leadership Quarterly's (
LQ) first decade as a premier outlet for scholarly leadership research, we review 353 articles published in
LQ during ...its second decade. Multiple methods were employed to prepare this review, including: interviews with the journal's current Senior Editor and Associate Editors; an assessment of
LQ's impact, reputation, and most cited articles through citation analyses; a content analysis of article type (theory, empirical, and methods), contributors (e.g., discipline, nationality, and institutional affiliation), theoretical foundations, research strategies, sample location/type, data collection methods, and analytical procedures; survey and follow-up focus groups conducted with
LQ Editorial Review Board members; and qualitative analyses to assess the prevalent themes, contributions, and trends reflected in
LQ during its second decade. Drawing from these sources, we describe anticipated directions for future research.
Aims/hypothesis
Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher ...maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal ‘metabolically favourable adiposity’ on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI).
Methods
To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (
n
= 442,278 and
n
= 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (
n
= 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total
n
= 9323 mother–child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers.
Results
Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (−94 95% CI −150, −38 g per 1 SD 6.5% higher maternal metabolically favourable adiposity,
p
= 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 95% CI 16, 53 g per 1 SD 4 kg/m
2
higher maternal BMI,
p
= 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it.
Conclusions/interpretation
Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile.
Data availability
The data for the genome-wide association studies (GWAS) of BMI are available at
https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files
. The data for the GWAS of body fat percentage are available at
https://walker05.u.hpc.mssm.edu
.
Graphical abstract
Summary
Background
Cord blood (CB) leptin is positively associated with adiposity at birth, but the association with child adiposity is unclear.
Objectives
We hypothesized that CB leptin is ...positively associated with adiposity in peripubertal children and with childhood leptin.
Methods
Leptin was measured in 986 CB and 931 childhood stored samples from a prospective birth cohort. Adiposity measures were collected at birth and mean age 11.5 years. Linear and logistic regression analyses were used to evaluate associations between log‐transformed CB leptin and neonatal and childhood adiposity measures as continuous and categorical variables, respectively.
Results
CB leptin was positively associated with neonatal and childhood adiposity. Childhood associations were attenuated when adjusted for maternal body mass index (BMI) and glucose, but remained statistically significant for childhood body fat percentage (β = 1.15%, confidence interval CI = 0.46–1.84), body fat mass (β = 0.69 kg, 95% CI = 0.16–1.23), sum of skin‐folds (β = 1.77 mm, 95% CI = 0.31–3.24), log‐transformed child serum leptin (β = 0.13, 95% CI = 0.06–0.20), overweight/obesity (OR = 1.21, 95% CI = 1.03–1.42), obesity (OR = 1.31, 95% CI = 1.04–1.66) and body fat percentage >85th percentile (OR = 1.38, 95% CI = 1.12–1.73). Positive associations between newborn adiposity measures and CB leptin confirmed previous reports.
Conclusion
CB leptin is positively associated with neonatal and childhood adiposity and child leptin levels, independent of maternal BMI and maternal hyperglycemia. CB leptin may be a biomarker of future adiposity risk.
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