Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Background So far, more than 170 loci have been associated with circulating lipid levels through genomewide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ~60 000 individuals in the discovery stage and ~90 000 samples in the replication stage. Results Our study resu

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

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

Numerical modeling of the geomechanical response of a rock mass to a radioactive waste repository

Geotechnical numerical models capable of predicting the thermomechanical response and groundwater movements around an underground radioactive waste repository are vital to the success of the nuclear waste disposal program. In the absence of directly related engineering experience, the design, risk assessment, and licensing procedures of a repository will be reliant on predictions made using such models. This paper reviews models being used to assist in repository design and summarizes the results of a recent parametric study of underground disposal in basaltic rocks. On the basis of preliminary site data, it is concluded that the allowable areal density of heat-generating waste will be controlled by the stability of placement rooms and the boreholes in which waste canisters are placed. Regional effects including thermally induced upward groundwater flow, appear to present less severe problems

Relationship between variability of the semidiurnal tide in the Northern Hemisphere mesosphere and quasi-stationary planetary waves throughout the global middle atmosphere

To investigate possible couplings between planetary waves and the semidiurnal tide (SDT), this work examines the statistical correlations between the SDT amplitudes observed in the Northern Hemisphere (NH) mesosphere and stationary planetary wave (SPW) with wavenumber S=1 (SPW1) amplitudes throughout the global stratosphere and mesosphere. The latter are derived from the Aura-MLS temperature measurements. During NH summer-fall (July–October), the mesospheric SDT amplitudes observed at Svalbard (78° N) and Eureka (80° N) usually do not show persistent correlations with the SPW1 amplitudes in the opposite hemisphere. Although the SDT amplitudes observed at lower latitudes (~50–70° N), especially at Saskatoon (52° N), are often shown to be highly and positively correlated with the SPW1 amplitudes in high southern latitudes, these correlations cannot be sufficiently explained as evidence for a direct physical link between the Southern Hemisphere (SH) winter-early spring SPW and NH summer-early fall mesospheric SDT. This is because the migrating tide's contribution is usually dominant in the mid-high latitude (~50–70° N) NH mesosphere during the local late summer-early fall (July–September). The numerical correlation is dominated by similar low-frequency variability or trends between the amplitudes of the NH SDT and SH SPW1 during the respective equinoctial transitions. In contradistinction, during NH winter (November–February), the mesospheric SDT amplitudes at northern mid-high latitudes (~50–80° N) are observed to be significantly and positively correlated with the SPW1 amplitudes in the same hemisphere in most cases. Because both the SPW and migrating SDT are large in the NH during the local winter, a non-linear interaction between SPW and migrating SDT probably occurs, thus providing a global non-migrating SDT. This is consistent with observations of SDT in Antarctica that are large in summer than in winter. It is suggested that climatological hemispheric asymmetry, e.g. the SH and NH winter characteristics are substantially different, lead to differences in the inter-hemispheric SPW-tide physical links

Toward the Development of an Urban Growth Model that Recognizes the Importance of the Basic Nature of Services

This exploratory research examines selected service sectors of a defined local economy. Using export base theory, preliminary models linking these services sectors to exogenous influences are developed. These models are found to be statistically diverse. Further model-building efforts should recognize the heterogeneous nature of services through disaggregation of services sectors and a thorough consideration of potential exogenous variables. Copyright American Real Estate and Urban Economics Association.