Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, ...including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
It is widely believed that high-temperature superconductivity in the cuprates emerges from doped Mott insulators1. When extra carriers are inserted into the parent state, the electrons become mobile ...but the strong correlations from the Mott state are thought to surviveinhomogeneous electronic order, a mysterious pseudogap and, eventually, superconductivity appear. How the insertion of dopant atoms drives this evolution is not known, nor is whether these phenomena are mere distractions specic to hole-doped cuprates or represent genuine physics of doped Mott insulators. Here we visualize the evolution of the electronic states of (Sr1xLax)2IrO4, which is an effective spin-1/2 Mott insulator like the cuprates, but is chemically radically dierent2,3. Using spectroscopic-imaging scanning tunnelling microscopy (SI-STM), we nd that for a doping concentration of x 5%, an inhomogeneous, phase-separated state emerges, with the nucleation of pseudogap puddles around clusters of dopant atoms. Within these puddles, we observe the same iconic electronic order that is seen in underdoped cuprates1,49. We investigate the genesis of this state and nd evidence at low doping for deeply trapped carriers, leading to fully gapped spectra, which abruptly collapse at a threshold of x4%. Our results clarify the melting of the Mott state, and establish phase separation and electronic order as generic features of doped Mott insulators.
The Strait of Georgia, Canada, has complex interactions among natural and human pressures that confound understanding of changes in this system. We report on the interannual variability in biomass of ...12 zooplankton taxonomic groups in the deep (bottom depths greater than 50 m) central and northern Strait of Georgia from 1996 to 2018, and their relationships with 10 physical variables. Total zooplankton biomass was dominated (76%) by large-sized crustaceans (euphausiids, large and medium size calanoid copepods, amphipods). The annual anomaly of total zooplankton biomass was highest in the late 1990s, lowest in the mid-2000s, and generally above its climatological (1996-2010) average after 2011, although many individual groups had different patterns. Two latent trends (derived from dynamic factor analyses) described the variability of annual biomass anomalies underlying all zooplankton groups: a U-shaped trend with its minimum in the mid-2000s, and a declining trend from 2001 to 2011. Two latent trends also described the physical variables. The variability represented by these four latent trends clustered into two periods: 1996-2006, with generally declining zooplankton biomass and increasing salinities, and 2007-2018, with increasing zooplankton biomass and decreasing salinities. ARIMA modelling showed sea surface salinity at Entrance Island in the middle Strait of Georgia, the Pacific Decadal Oscillation, and the peak date of the spring phytoplankton bloom were significantly related to the two latent zooplankton trends. ARIMA models comparing zooplankton and physical variables with the marine survivals of four salmon populations which enter the Strait as juveniles (Chinook: Cowichan River, Puntledge River, Harrison River; Coho: Big Qualicum River) all included zooplankton groups consistent with known salmon prey; prominent among the physical variables were sea surface salinity and variables representing the flow from the Fraser River. These regressions explained (adjR2) 38 to 85% of the annual variability in marine survival rates of these salmon populations over the study time period. Although sea temperature was important in some relationships between zooplankton biomass and salmon marine survival, salinity was a more frequent and more important variable, consistent with its influence on the hydrodynamics of the Strait of Georgia system.
We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome ...sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.
Many exotic compounds, such as cuprate superconductors and heavy fermion materials, exhibit a linear in temperature (T) resistivity, the origin of which is not well understood. We found that the ...resistivity of the quantum critical metal Sr(3)Ru(2)O(7) is also T-linear at the critical magnetic field of 7.9 T. Using the precise existing data for the Fermi surface topography and quasiparticle velocities of Sr(3)Ru(2)O(7), we show that in the region of the T-linear resistivity, the scattering rate per kelvin is well approximated by the ratio of the Boltzmann constant to the Planck constant divided by 2π. Extending the analysis to a number of other materials reveals similar results in the T-linear region, in spite of large differences in the microscopic origins of the scattering.
Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are ...complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets.
Topological order is often quantified in terms of Chern numbers, each of which classifies a topological singularity. Here, inspired by concepts from high-energy physics, we use quantum simulation ...based on the spin degrees of freedom of atomic Bose-Einstein condensates to characterize a singularity present in five-dimensional non-Abelian gauge theories-a Yang monopole. We quantify the monopole in terms of Chern numbers measured on enclosing manifolds: Whereas the well-known first Chern number vanishes, the second Chern number does not. By displacing the manifold, we induce and observe a topological transition, where the topology of the manifold changes to a trivial state.
The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study ...participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P < 5 × 10
) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation.
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