BACKGROUND:Maternal self-reported ethnicity (SRE) is associated with pre-eclampsia (PE) risk and is included in prediction models. OBJECTIVES:The objectives of the study were to examine whether genetic ancestry estimates are associated with PE and improve the FMF (Fetal Medicine Foundation) PE risk model performance. METHODS:PE cases and matched controls from the Harris-Birthright Cohort were genotyped using the Illumina Global Screening Array. Genetic ancestries were estimated using a multiethnic reference panel. African genetic ancestries were incorporated into logistic regression models alongside established clinical risk factors. Area under receiver operating characteristic curves of FMF models with and without genetic ancestries was compared. RESULTS:This case-control study included 5,207 women: 3,513 White (1,382 PE cases, 2,131 controls) and 1,694 Black SRE (745 PE cases, 949 controls). Ethnicity-ancestry discrepancy was present in 11.3% of self-reporting Black and 5.3% of self-reporting White individuals. Higher West African genetic ancestry was independently associated with increased PE odds. Among self-reporting White women, those with 50% to 100% West African (AFR) ancestry had higher risk vs those with <5% (adjusted OR: 6.46; 95% CI: 3.37 to 12.98; P < 0.001). In self-reporting Black women, lower West AFR ancestry (50% to 84.9%) reduced risk vs those with 85% to 100% (adjusted OR: 0.60; 95% CI: 0.45-0.80; P < 0.001). Incorporating genetic ancestry did not improve FMF model performance. CONCLUSIONS:SRE imperfectly represents genetic ancestry in multiethnic populations. West AFR ancestry independently associates with the PE risk, supporting biological relevance of ancestry-based stratification. However, genetic ancestry did not improve the gold-standard clinical prediction model performance. Large genomic studies in multiethnic cohorts are needed to delineate the genetic architecture of PE.

Supplementary Methods and Supplementary Figures S1–S11

The potential for DMI measurements of deuterated glucose metabolism to differentiate between metabolic subtypes in GBM has been demonstrated in patient-derived xenografts in mice. The glycolytic subtype showed increased lactate labelling whereas two oxidative subtypes showed increased glutamate/glutamine (Glx) labelling. There was decreased lactate labelling in a glycolytic subtype and decreased lactate and Glx labelling in an oxidative subtype within 24 h after the completion of standard-of-care chemoradiotherapy, demonstrating that the technique can also be used to detect early treatment response in this tumor type.

Coil-localized 2H MRS differentiates metabolic subtypes of GBM in vivo. A-E, Representative summed 5-minute 2H spectra from tumor-free mice (A) and tumor-bearing mice with A11 (B), U87 (C), S2 (D), and AT5 tumors (E) acquired over a period of 60 minutes following an i.v. injection of 2 g/kg [6,6′-2H2]glucose. The summed spectra overlaid with the corresponding peak fits are shown. F-I, Concentrations of HDO (F), glucose (G), Glx (H), and lactate (I) determined from the fitted peaks in individual 5-minute spectra. J-L, The average concentrations of 2H-labeled glucose (J), Glx (K), and lactate (L) measured between 20 and 65 minutes following injection of [6,6′-2H2] glucose in the four tumor models and in tumor-free animals. A one-way ANOVA showed that there were no significant differences in the labeled glucose concentration in the four tumor models and in tumor-free mice, but there were significant differences in the concentrations of labeled lactate and Glx between the glycolytic and mitochondrial subtype tumors and between the concentrations of labeled lactate in the glycolytic subtype tumors and the tumor-free animals. ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Histologic assessment of tumor cell proliferation and cell death before and 24 hours after treatment. A-D, Representative sections of A11 and S2 tumors stained for Ki67 (A and B) and CC3 (C and D) pre- and posttreatment with chemoradiation. E-H, The percentage of Ki67-positive cells for A11 (E) and S2 (F) tumors and the percentage of CC3-positive cells for A11 (G) and S2 (H) tumors before and at 24 hours after completion of treatment. **, P < 0.01; ***, P < 0.001.

Metabolic characterization of GBM tumor cells in vitro. A, ECAR measurements. There were no significant differences between A11 and U87 cells (P = 0.427) or between S2 and AT5 cells (P = 0.494). B, OCR measurements. There were no significant differences between S2 and AT5 cells (P = 0.920) or between A11 and U87 cells (P = 0.127). C, OCR/ECAR ratio. There were no significant differences between S2 and AT5 cells (P = 0.996) or between A11 and U87 cells (P = 0.378). D,2H MRS measurements of 2H-labeled lactate produced by A11, S2, and AT5 cells incubated for 4 hours in glucose-free neurobasal media and U87 cells incubated in glucose-free DMEM, both supplemented with 10 mmol/L [6,6′-2H2]glucose. E and F, HSQC 1H-13C MRS measurements of 13C-labeled lactate (E) and Glx (F) measured in cell extracts obtained by chloroform–methanol extraction following incubation for 6 hours in glucose-free media supplemented with 10 mmol/L [U-13C]glucose. Proton signal intensities in the spectra are reported relative to the TMSP standard. ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

3D 2H CSI of [6,6-2H2]glucose metabolism in A11 and S2 tumors, in normal-appearing brain tissue, and in brain tissue in tumor-free mice. A-C, Representative spectrum from a voxel within the brain of a tumor-free mouse (A), and representative spectra from voxels within the tumor and normal-appearing brain of A11 (B) and S2 (C) tumor–bearing animals injected with 2 g/kg [6,6-2H2]glucose. Fits to the spectra are shown in color: red, water; green, glucose; blue, Glx; and purple, lactate. The tumor is outlined in yellow on the T2-weighted 1H image. The locations of the CSI voxels are indicated by the boxes. The spectra are the sum of six 10-minute spectra acquired from 3 × 3 × 9 mm voxels. D-F, Comparison of 2H-labeled glucose (D), Glx (E), and lactate (F) concentrations in the brains of tumor-free mice and the normal-appearing brain of mice bearing A11 and S2 tumors. G-I, Comparison of 2H-labeled glucose (G), Glx (H), and lactate (I) concentrations in A11 tumors and adjacent normal-appearing brain tissue. J-L, Comparison of 2H-labeled glucose (J), Glx (K), and lactate (L) concentrations in S2 tumors and adjacent normal-appearing brain tissue. ns, not significant; *, P < 0.05; ***, P < 0.001.

Spectroscopic measurements of the effects of chemoradiation on glucose metabolism in tumor models representative of the glycolytic and mitochondrial subtypes. Serial 5-minute tumor 2H spectra were acquired following an i.v. injection of [6,6′-2H2]glucose in two glycolytic subtypes of GBM (A11 and U87; A–H) and two mitochondrial subtypes (S2 and AT5; I–P) before and 24 hours after targeted chemoradiotherapy. Measurements of 2H-labeled lactate and Glx in serial 5-minute spectra acquired from tumor-bearing animals pre- and posttreatment of A11 (A and B), U87 (C and D), S2 (I and J), and AT5 (K and L) tumors. The concentrations of 2H-labeled lactate and Glx measured between 20 and 65 minutes following [6,6′-2H2]glucose injection were compared pre- and posttreatment in A11 (E and F), U87 (G and H), S2 (M and N), and AT5 (O and P) tumor–bearing animals. ns, not significant; *, P < 0.05; ****, P < 0.0001.

Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H2O2 production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6brd1/rd1; Prhp2rds/rds; RPGR-/-; Cln6nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT-/-, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR-/- mice. These findings have important implications for the mechanism and treatment of RP.

<p>Supplementary Table and Figures</p>

PURPOSE. Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. METHODS. Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. RESULTS. Critical age for the initiation of photoreceptor loss ranged from 48 years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25 mu m in the extrafoveal retina and 19 mu m in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. CONCLUSIONS. Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

<p>This file presents the raw data for the cell free DNA experiments.</p>

This file presents demographic information across the different PDOX populations.

Cell death is an important imaging target for assessing early tumour treatment response and the effectiveness of therapy. We show here that 2 H-labelled fumarate can be administered orally to detect cell death and assess early tumour treatment response in a subcutaneous lymphoma (EL4) model. Following oral gavage, 2 H spectra were acquired from tumors with a time resolution of 5 min. Within 48h after chemotherapeutic drug (etoposide) treatment the tumor malate/fumarate signal ratios increased similarly to those measured after intravenous injection.

ABSTRACTCommon SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.