Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Deficits in tactile learning in a mouse model of fragile X syndrome.

The fragile X mental retardation 1 mutant mouse (Fmr1 KO) recapitulates several of the neurologic deficits associated with Fragile X syndrome (FXS). As tactile hypersensitivity is a hallmark of FXS, we examined the sensory representation of individual whiskers in somatosensory barrel cortex of Fmr1 KO and wild-type (WT) mice and compared their performance in a whisker-dependent learning paradigm, the gap cross assay. Fmr1 KO mice exhibited elevated responses to stimulation of individual whiskers as measured by optical imaging of intrinsic signals. In the gap cross task, initial performance of Fmr1 KO mice was indistinguishable from WT controls. However, while WT mice improved significantly with experience at all gap distances, Fmr1 KO mice displayed significant and specific deficits in improvement at longer distances which rely solely on tactile information from whiskers. Thus, Fmr1 KO mice possess altered cortical responses to sensory input that correlates with a deficit in tactile learning

Spontaneous oscillations in intrinsic signals reveal the structure of cerebral vasculature

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The Gap Cross task is a whisker-dependent sensory learning paradigm.

<p>(A) Schematic of the gap cross learning task. Motion sensors positioned at four points along the 2 platforms (labeled #1–4) track the mouse as it moves from the starting platform across a given gap distance to the target platform. (B) Activation of each sensor (grey box) indicates the position of the mouse. (C) Successful crosses are defined as the movement of the mouse from the starting platform to the target platform (green circles). Failures are defined as trials in which the mouse approaches the edge of the home or target platform and returns to the back of the home platform (red crosses).</p

<i>Fmr1</i> KO mice display normal learning on the gap cross assay at shorter gap distances but impaired learning at longer whisker-dependent distances.

<p>(A) The percent successful crosses averaged across the first six sessions and subsequent six sessions across gap distances ranging from 3.0 cm to 6.0 cm for both wild-type mice (black lines, n = 6) and <i>Fmr1</i> KO mice (blue lines, n = 9). For each distance, the line marker on the <i>left</i> is the average success rate of the first six sessions and the connected line marker on the <i>right</i> is the average success rate of the subsequent six sessions. Error bars represent standard error of the mean. (B) At shorter ‘nose’ distances, both wild-type (WT) and Fmr1 KO mice (KO) improve to a greater percentage of successful crosses between the average of the first six sessions (WT, grey, KO light blue) and the last six sessions (WT, black, KO dark blue). This improvement is statistically significant (WT, p = .007; n = 6; KO, p<.001, n = 9; WT; two-way ANOVA) (C) At whisker-dependent distances, wild-type (WT) improve between early sessions (grey line) and subsequent sessions (black line) despite the lower overall success rate at increasing gap distances. However, KO mice do not display significant improvement between early sessions (light blue line) and later sessions (dark blue line) (WT, p = .002, n = 6, KO, p = .14; n = 9, two-way ANOVA). (D) Average improvement for WT and KO mice at shorter ‘nose’ distances and longer ‘whisker’ distances. WT mice display significantly greater improvement at whisker-dependent distances that KO mice (p = .02, two-tailed t-test).</p

<i>Fmr1 KO</i> mice exhibit increased evoked activity in primary somatosensory cortex during whisker stimulation.

<p>(A) Schematic showing experimental set up of intrinsic optical imaging over primary somatosensory cortex (black circle) during periodic whisker stimulation. (B) Pictures of the thin skull preparation and example images collected from a wild-type (WT) mouse (left) and <i>Fmr1</i> KO mouse (right) mouse. Scale bar = 0.4 mm. Rostral (R), Caudal (C), Lateral (L) and Medial (M) coordinates are shown. (C) Representative examples of data collected during a typical imaging session. Above, a time series of pixel values for the cortical location indicated by the asterisk in the <i>Fmr1</i> KO in panel B. Below, a fast-fourier transform (FFT) of the raw trace extracts the magnitude of the change in reflectance (ΔR/R) corresponding to the frequency of whisker stimulation (red square). (D) The number of pixels within the region of response with ΔR/R magnitudes greater than the threshold indicated on the abscissa for WT (n = 10) and <i>Fmr1</i> KO (n = 10) mice. The response to whisker stimulation is elevated in <i>Fmr1</i> KO mice (WT vs. KO, p = .011; 2-way ANOVA).</p

Nogo receptor 1 limits tactile task performance independent of basal anatomical plasticity.

The genes that govern how experience refines neural circuitry and alters synaptic structural plasticity are poorly understood. The nogo-66 receptor 1 gene (ngr1) is one candidate that may restrict the rate of learning as well as basal anatomical plasticity in adult cerebral cortex. To investigate if ngr1 limits the rate of learning we tested adult ngr1 null mice on a tactile learning task. Ngr1 mutants display greater overall performance despite a normal rate of improvement on the gap-cross assay, a whisker-dependent learning paradigm. To determine if ngr1 restricts basal anatomical plasticity in the associated sensory cortex, we repeatedly imaged dendritic spines and axonal varicosities of both constitutive and conditional adult ngr1 mutant mice in somatosensory barrel cortex for two weeks through cranial windows with two-photon chronic in vivo imaging. Neither constant nor acute deletion of ngr1 affected turnover or stability of dendritic spines or axonal boutons. The improved performance on the gap-cross task is not attributable to greater motor coordination, as ngr1 mutant mice possess a mild deficit in overall performance and a normal learning rate on the rotarod, a motor task. Mice lacking ngr1 also exhibit normal induction of tone-associated fear conditioning yet accelerated fear extinction and impaired consolidation. Thus, ngr1 alters tactile and motor task performance but does not appear to limit the rate of tactile or motor learning, nor determine the low set point for synaptic turnover in sensory cortex