Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

The Atacama Cosmology Telescope: CMB Polarization at 200<ℓ<9000200<\ell<9000

We report on measurements of the cosmic microwave background (CMB) and celestial polarization at 146 GHz made with the Atacama Cosmology Telescope Polarimeter (ACTPol) in its first three months of observing. Four regions of sky covering a total of 270 square degrees were mapped with an angular resolution of $1.3'$. The map noise levels in the four regions are between 11 and 17 $\mu$K-arcmin. We present TT, TE, EE, TB, EB, and BB power spectra from three of these regions. The observed E-mode polarization power spectrum, displaying six acoustic peaks in the range $200<\ell<3000$, is an excellent fit to the prediction of the best-fit cosmological models from WMAP9+ACT and Planck data. The polarization power spectrum, which mainly reflects primordial plasma velocity perturbations, provides an independent determination of cosmological parameters consistent with those based on the temperature power spectrum, which results mostly from primordial density perturbations. We find that without masking any point sources in the EE data at $\ell<9000$, the Poisson tail of the EE power spectrum due to polarized point sources has an amplitude less than $2.4$ $\mu$K$^2$ at $\ell = 3000$ at 95\% confidence. Finally, we report that the Crab Nebula, an important polarization calibration source at microwave frequencies, has 8.7\% polarization with an angle of $150.7^\circ \pm 0.6^\circ$ when smoothed with a $5'$ Gaussian beam.Comment: 16 pages, 15 figures, 5 table

Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value &lt; 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel&nbsp;loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p &lt; 5 × 10−8) and suggestive (p &lt; 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Conservation of resources theory and research use in health systems

<p>Abstract</p> <p>Background</p> <p>Health systems face challenges in using research evidence to improve policy and practice. These challenges are particularly evident in small and poorly resourced health systems, which are often in locations (in Canada and globally) with poorer health status. Although organizational resources have been acknowledged as important in understanding research use resource theories have not been a focus of knowledge translation (KT) research. What resources, broadly defined, are required for KT and how does their presence or absence influence research use?</p> <p>In this paper, we consider conservation of resources (COR) theory as a theoretical basis for understanding the capacity to use research evidence in health systems. Three components of COR theory are examined in the context of KT. First, resources are required for research uptake. Second, threat of resource loss fosters resistance to research use. Third, resources can be optimized, even in resource-challenged environments, to build capacity for KT.</p> <p>Methods</p> <p>A scan of the KT literature examined organizational resources needed for research use. A multiple case study approach examined the three components of COR theory outlined above. The multiple case study consisted of a document review and key informant interviews with research team members, including government decision-makers and health practitioners through a retrospective analysis of four previously conducted applied health research studies in a resource-challenged region.</p> <p>Results</p> <p>The literature scan identified organizational resources that influence research use. The multiple case study supported these findings, contributed to the development of a taxonomy of organizational resources, and revealed how fears concerning resource loss can affect research use. Some resources were found to compensate for other resource deficits. Resource needs differed at various stages in the research use process.</p> <p>Conclusions</p> <p>COR theory contributes to understanding the role of resources in research use, resistance to research use, and potential strategies to enhance research use. Resources (and a lack of them) may account for the observed disparities in research uptake across health systems. This paper offers a theoretical foundation to guide further examination of the COR-KT ideas and necessary supports for research use in resource-challenged environments.</p