13 research outputs found
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
Perceiving depth order during pursuit eye movement
Pursuit eye movements alter retinal motion cues to depth. For instance, the sinusoidal retinal velocity profile produced by a translating, corrugated surface resembles a sinusoidal shear during pursuit. One way to recover the correct spatial phase of the corrugationÕs profile (i.e. which part is near and which part is far) is to combine estimates of shear with extra-retinal estimates of translation. In support of this hypothesis, we found the corrugationÕs spatial phase appeared ambiguous when retinal shear was viewed without translation, but unambiguous when translated and viewed with or without a pursuit eye movement. The eyes lagged the sinusoidal translation by a small but persistent amount, raising the possibility that retinal slip could serve as the disambiguating cue in the eye-moving condition. A yoked control was therefore performed in which measured horizontal slip was fed back into a fixated shearing stimulus on a trial-by-trial basis. The results showed that the corrugationÕs phase was only seen unambiguously during the real eye movement. This supports the idea that extra-retinal estimates of eye velocity can help disambiguate ordinal depth structure within moving retinal images
Head-centred motion perception in the ageing visual system
Stationary objects appear to move in the opposite direction to a pursuit eye movement (Filehne illusion) and moving objects appear slower when pursued (Aubert-Fleischl phenomenon). Both illusions imply that extra-retinal, eye-velocity signals lead to lower estimates of speed than corresponding retinal motion signals. Intriguingly, the velocity (i.e. speed and direction) of the Filehne illusion depends on the age of the observer, especially for brief display durations (Wertheim and Bekkering, 1992). This suggests relative signal size changes as the visual system matures. To test the signal-size hypothesis, we compared the Filehne illusion and Aubert-Fleischl phenomenon in young and old observers using short and long display durations. The trends in the Filehne data were similar to those reported by Wertheim and Bekkering. However, we found no evidence for an effect of age or duration in the Aubert-Fleischl phenomenon. The differences between the two illusions could not be reconciled on the basis of actual eye movements made. The findings suggest a more complicated explanation of the combined influence of age and duration on head-centred motion perception than that described by the signal-size hypothesis
Pharmaceutical, cellular and genetic therapies for Huntington's disease
HD (Huntington's disease) is a devastating neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the huntingtin protein. Presently, there is no known cure for HD and existing symptomatic treatments are limited. However, recent advances have identified multiple pathological mechanisms involved in HD, some of which have now become the focus of therapeutic intervention. In this review, we consider progress made towards developing safe and effective pharmaceutical-, cell- and genetic-based therapies, and discuss the extent to which some of these therapies have been successfully translated into clinical trials. These new prospects offer hope for delaying and possibly halting this debilitating disease
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Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY.
The unparalleled collection of clinical data and biomaterials within the EHDN's REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments
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Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation
Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Funder: Cardiac Society of Australia and New Zealand (CSANZ); doi: https://doi.org/10.13039/501100001173Funder: Société Française de Cardiologie (French Society of Cardiology); doi: https://doi.org/10.13039/501100005630Funder: Heart and Stroke Foundation of Canada (Heart and Stroke Foundation); doi: https://doi.org/10.13039/100004411Funder: Mayo Clinic; doi: https://doi.org/10.13039/100000871Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions
Nat Genet
Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions
Recommended from our members
Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.
Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions