New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

<div><p>Threatened preterm labor (TPTL) is defined as persistent premature uterine contractions between 20 and 37 weeks of gestation and is the most common condition that requires hospitalization during pregnancy. Most of these TPTL women continue their pregnancies to term while only an estimated 5% will deliver a premature baby within ten days. The aim of this work was to study differential whole blood gene expression associated with spontaneous preterm birth (sPTB) within 48 hours of hospital admission. Peripheral blood was collected at point of hospital admission from 154 women with TPTL before any medical treatment. Microarrays were utilized to investigate differential whole blood gene expression between TPTL women who did (n = 48) or did not have a sPTB (n = 106) within 48 hours of admission. Total leukocyte and neutrophil counts were significantly higher (35% and 41% respectively) in women who had sPTB than women who did not deliver within 48 hours (<i>p</i><0.001). Fetal fibronectin (fFN) test was performed on 62 women. There was no difference in the urine, vaginal and placental microbiology and histopathology reports between the two groups of women. There were 469 significant differentially expressed genes (FDR<0.05); 28 differentially expressed genes were chosen for microarray validation using qRT-PCR and 20 out of 28 genes were successfully validated (<i>p</i><0.05). An optimal random forest classifier model to predict sPTB was achieved using the top nine differentially expressed genes coupled with peripheral clinical blood data (sensitivity 70.8%, specificity 75.5%). These differentially expressed genes may further elucidate the underlying mechanisms of sPTB and pave the way for future systems biology studies to predict sPTB.</p></div

Receiver operator characteristics curves displaying the performances of the random forest classifier models.

<p>(<b>A</b>) Models using the top nine genes, with and without peripheral clinical blood data in 154 women. (<b>B</b>) Models developed using the top nine genes, fetal fibronectin (fFN) and clinical blood data in 62 women. The lines for nine genes only and nine genes with fFN are superimposed.</p

The dot plots (mean and standard deviations) of gestational age at presentation of women who did or did not have a spontaneous preterm birth (sPTB) within 48 hours of hospital admission in the microarray (A) and qRT-PCR (B) study, respectively.

<p>The dot plots (mean and standard deviations) of gestational age at presentation of women who did or did not have a spontaneous preterm birth (sPTB) within 48 hours of hospital admission in the microarray (A) and qRT-PCR (B) study, respectively.</p

Predicting spontaneous preterm birth within 48(with and without peripheral clinical blood data) and comparing the predictive efficacies of fetal fibronectin and the random forest classifier models (top 9 genes, with or without peripheral clinical blood data and fFN) to predict spontaneous preterm birth within 48 hours in 62 women.

<p>Predicting spontaneous preterm birth within 48(with and without peripheral clinical blood data) and comparing the predictive efficacies of fetal fibronectin and the random forest classifier models (top 9 genes, with or without peripheral clinical blood data and fFN) to predict spontaneous preterm birth within 48 hours in 62 women.</p

Urine culture, vaginal microbiology and placental histopathology and microbiologic assessments of participants.

<p>Urine culture, vaginal microbiology and placental histopathology and microbiologic assessments of participants.</p

This heat map of the top 50 differentially expressed genes (highest fold changes) displays the hierarchical clustering, consistency and regulation of the gene expression levels.

<p>Elevated gene expressions are indicated in green; down-regulated gene expressions are indicated in red. The colors on the top bars represent women who had a spontaneous preterm birth within 48 hours (red), preterm delivery between 2 to 7 days (green), preterm delivery between 7 days and within 37 weeks of gestation (blue) and women who delivered at term (yellow).</p

Receiver operator characteristics curves displaying the performances of the random forest classifier models.

<p>(<b>A</b>) Models using the top nine genes, with and without peripheral clinical blood data in 154 women. (<b>B</b>) Models developed using the top nine genes, fetal fibronectin (fFN) and clinical blood data in 62 women. The lines for nine genes only and nine genes with fFN are superimposed.</p

Reactome Functional Interaction analysis of 469 significant genes revealed eight clusters consisting of at least five of genes.

<p>Each cluster is indicated by a different color and their representative GO slim term(s). Edges of “->” indicate activating/catalyzing; “-|” for inhibition; “-” for functional interactions extracted from complexes or inputs and “- - -” for predicted functional interactions.</p