Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

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

Fantasy Paradigms of Health Inequalities: utopian thinking?

This paper argues that, while it can be politically expedient for governments to engage with health inequalities, they cannot, within the confines of neoliberalism, realistically propose actions that evidence suggests will effectively reduce them - such as tackling power inequalities, social status and connections or class inequality. Indeed, a dominant 'policy paradigm' prioritising economic growth restricts the ability of policy actors to imagine alternative, more equitable scenarios. In this context, some policy actors and researchers have devised a parallel fantasy world in which proximal, downstream, easily-tackled exposures are posited as potential solutions to health inequalities. The consequence of this is a widespread public sector culture in which well-meaning policy-makers, practitioners, researchers and members of the public collude in sustaining a 'cargo cult' of health behaviourism. In examining this situation, we draw on accounts and critiques of utopian thinking to help explain: (i) the remarkable persistence of policy proposals to tackle health inequalities via downstream interventions, in spite of the strength of evidence challenging such approaches; and (ii) the limited extent to which more upstream proposals inform policy debates. We argue Ruth Levitas’ notion of ‘utopia as method’ offers an imaginative and potentially useful avenue for future health inequalities research

The Effect of Disruption of Prefrontal Cortical Function with Transcranial Magnetic Stimulation on Visual Working Memory

It is proposed that feedback signals from the prefrontal cortex (PFC) to extrastriate cortex are essential for goal-directed processing, maintenance, and selection of information in visual working memory (VWM). In a previous study, we found that disruption of PFC function with transcranial magnetic stimulation (TMS) in healthy individuals impaired behavioral performance on a face/scene matching task and decreased category-specific tuning in extrastriate cortex as measured with functional magnetic resonance imaging (fMRI). In this study, we investigated the effect of disruption of left inferior frontal gyrus (IFG) function on the fidelity of neural representations of two distinct information codes: (1) the stimulus category and (2) the goal-relevance of viewed stimuli. During fMRI scanning, subjects were presented face and scene images in pseudo-random order and instructed to remember either faces or scenes. Within both anatomical and functional regions of interest (ROIs), a multi-voxel pattern classifier was used to quantitatively assess the fidelity of activity patterns representing stimulus category: whether a face or a scene was presented on each trial, and goal relevance, whether the presented image was task relevant (i.e., a face is relevant in a "Remember Faces" block, but irrelevant in a "Remember Scenes" block). We found a reduction in the fidelity of the stimulus category code in visual cortex after left IFG disruption, providing causal evidence that lateral PFC modulates object category codes in visual cortex during VWM. In addition, we found that IFG disruption caused a reduction in the fidelity of the goal relevance code in a distributed set of brain regions. These results suggest that the IFG is involved in determining the task-relevance of visual input and communicating that information to a network of regions involved in further processing during VWM. Finally, we found that participants who exhibited greater fidelity of the goal relevance code in the non-disrupted right IFG after TMS performed the task with the highest accuracy

Dissociable neural mechanisms underlie currently-relevant, future-relevant, and discarded working memory representations.

In daily life, we use visual working memory (WM) to guide our actions. While attending to currently-relevant information, we must simultaneously maintain future-relevant information, and discard information that is no longer relevant. However, the neural mechanisms by which unattended, but future-relevant, information is maintained in working memory, and future-irrelevant information is discarded, are not well understood. Here, we investigated representations of these different information types, using functional magnetic resonance imaging in combination with multivoxel pattern analysis and computational modeling based on inverted encoding model simulations. We found that currently-relevant WM information in the focus of attention was maintained through representations in visual, parietal and posterior frontal brain regions, whereas deliberate forgetting led to suppression of the discarded representations in early visual cortex. In contrast, future-relevant information was neither inhibited nor actively maintained in these areas. These findings suggest that different neural mechanisms underlie the WM representation of currently- and future-relevant information, as compared to information that is discarded from WM

Multi-scale neural decoding and analysis

Objective. Complex spatiotemporal neural activity encodes rich information related to behavior and cognition. Conventional research has focused on neural activity acquired using one of many different measurement modalities, each of which provides useful but incomplete assessment of the neural code. Multi-modal techniques can overcome tradeoffs in the spatial and temporal resolution of a single modality to reveal deeper and more comprehensive understanding of system-level neural mechanisms. Uncovering multi-scale dynamics is essential for a mechanistic understanding of brain function and for harnessing neuroscientific insights to develop more effective clinical treatment. Approach. We discuss conventional methodologies used for characterizing neural activity at different scales and review contemporary examples of how these approaches have been combined. Then we present our case for integrating activity across multiple scales to benefit from the combined strengths of each approach and elucidate a more holistic understanding of neural processes. Main results. We examine various combinations of neural activity at different scales and analytical techniques that can be used to integrate or illuminate information across scales, as well the technologies that enable such exciting studies. We conclude with challenges facing future multi-scale studies, and a discussion of the power and potential of these approaches. Significance. This roadmap will lead the readers toward a broad range of multi-scale neural decoding techniques and their benefits over single-modality analyses. This Review article highlights the importance of multi-scale analyses for systematically interrogating complex spatiotemporal mechanisms underlying cognition and behavior