| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Kristanl, Matej, et al.
(författare)
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The Seventh Visual Object Tracking VOT2019 Challenge Results
- 2019
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Ingår i: 2019 IEEE/CVF INTERNATIONAL CONFERENCE ON COMPUTER VISION WORKSHOPS (ICCVW). - : IEEE COMPUTER SOC. - 9781728150239 ; , s. 2206-2241
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Konferensbidrag (refereegranskat)abstract
- The Visual Object Tracking challenge VOT2019 is the seventh annual tracker benchmarking activity organized by the VOT initiative. Results of 81 trackers are presented; many are state-of-the-art trackers published at major computer vision conferences or in journals in the recent years. The evaluation included the standard VOT and other popular methodologies for short-term tracking analysis as well as the standard VOT methodology for long-term tracking analysis. The VOT2019 challenge was composed of five challenges focusing on different tracking domains: (i) VOT-ST2019 challenge focused on short-term tracking in RGB, (ii) VOT-RT2019 challenge focused on "real-time" short-term tracking in RGB, (iii) VOT-LT2019 focused on long-term tracking namely coping with target disappearance and reappearance. Two new challenges have been introduced: (iv) VOT-RGBT2019 challenge focused on short-term tracking in RGB and thermal imagery and (v) VOT-RGBD2019 challenge focused on long-term tracking in RGB and depth imagery. The VOT-ST2019, VOT-RT2019 and VOT-LT2019 datasets were refreshed while new datasets were introduced for VOT-RGBT2019 and VOT-RGBD2019. The VOT toolkit has been updated to support both standard short-term, long-term tracking and tracking with multi-channel imagery. Performance of the tested trackers typically by far exceeds standard baselines. The source code for most of the trackers is publicly available from the VOT page. The dataset, the evaluation kit and the results are publicly available at the challenge website(1).
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| 5. |
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| 6. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 7. |
- Schuettpelz, Eric, et al.
(författare)
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A community-derived classification for extant lycophytes and ferns
- 2016
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Ingår i: Journal of Systematics and Evolution. - : Wiley. - 1674-4918 .- 1759-6831. ; 54:6, s. 563-603
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Tidskriftsartikel (refereegranskat)abstract
- Phylogeny has long informed pteridophyte classification. As our ability to infer evolutionary trees has improved, classifications aimed at recognizing natural groups have become increasingly predictive and stable. Here, we provide a modern, comprehensive classification for lycophytes and ferns, down to the genus level, utilizing a community-based approach. We use monophyly as the primary criterion for the recognition of taxa, but also aim to preserve existing taxa and circumscriptions that are both widely accepted and consistent with our understanding of pteridophyte phylogeny. In total, this classification treats an estimated 11 916 species in 337 genera, 51 families, 14 orders, and two classes. This classification is not intended as the final word on lycophyte and fern taxonomy, but rather a summary statement of current hypotheses, derived from the best available data and shaped by those most familiar with the plants in question. We hope that it will serve as a resource for those wanting references to the recent literature on pteridophyte phylogeny and classification, a framework for guiding future investigations, and a stimulus to further discourse.
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| 8. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 9. |
- Eliasson, Jens, et al.
(författare)
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A power management architecture for sensor nodes
- 2007
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Ingår i: IEEE Wireless Communications & Networking Conference. - Piscataway, NJ : IEEE Communications Society. - 1424406587 ; , s. 3008-3013
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Konferensbidrag (refereegranskat)abstract
- Wireless sensor nodes are a versatile, generalpurpose technology capable of measuring, monitoring and controlling their environment. Even though sensor nodes are becoming ever smaller and more power efficient, there is one area that is not yet fully addressed; Power Supply Units (PSUs). Standard solutions that are efficient enough for electronic devices with higher power consumption than sensor nodes, such as mobile phones or PDAs, may prove to be ill suited for the extreme low-power and size requirements often found on wireless sensor nodes. In this paper, a system-level design of a Power Management Architecture (PMA) is presented. The PMA is an integration of PSU hardware and various software components, and is capable of supplying a sensor node with energy from multiple sources, as well as providing status information from the PSU. The heart of the architecture is a context- and power-aware Task manager, which controls when the nodes low-power modes are activated, and is highly integrated with PSU hardware as well as other software components in the system. Its main responsibility is to schedule when energy consuming tasks can be dispatched. Depending on the task priority and system configuration, a task can be either dispatched, discarded or delayed. This approach ensures that only critical tasks will be allowed to use the battery, and that the system will be powered by renewable energy when performing other non-critical tasks.
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| 10. |
- Eliasson, Jens, et al.
(författare)
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PCB Integration of Dye-sensitised Solar Cells for Internet of Things Applications
- 2012
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Ingår i: International Journal on Advances in Systems and Measurements. - 1942-261X. ; 5:1-2, s. 45-54
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Tidskriftsartikel (refereegranskat)abstract
- Internet of Things is envisioned to drastically chance the way sensor data from physical phenomena can be utilized by users on the Internet. However, one concern in deploying and maintaining a large number of sensor nodes is that replacing spent batteries will not be feasible. One solution to this issue may involve utilising energy harvesting technologies, e.g. solar, heat, or vibration, withsolar being the most promising for general applications. However, using solar panels is currently a relatively expensive approach as they require a time-consuming and therefore costly assembly process. As an alternative, this paper suggests a new approach to powering networked sensors: the direct integration of a solar cell onto a sensor nodes printed circuit board. This approach eliminates the need for manual assembly and the use of expensive connectors.
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| 11. |
- Eliasson, Jens, et al.
(författare)
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PCB Integration of dye-sensitised solar cells for low-cost networked embedded systems
- 2011
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Ingår i: SENSORCOMM. - 9781612081441 ; , s. 215-222
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Konferensbidrag (refereegranskat)abstract
- Wireless sensor networks are envisioned to make a large impact on how sensor data from physical phenomena can be utilized by millions of users on the Internet. However, one concern in deploying a large number of real-world physical sensors is that replacing spent batteries might not be feasible. One solution to this issue may involve energy harvesting technology, e.g. solar panels. Solar panels are currently relatively expensive because they require a time-consuming and therefore costly assembly process. As an alternative, this paper suggests a new approach to powering networked sensors: the direct integration of a solar cell onto the sensor nodes printed circuit board. This approach eliminates the need for manual assembly and the use of expensive connectors. This article presents test results and a feasibility analysis of the direct integration of a dye-sensitised solar cell onto a circuit board. Preliminary results indicate that this approach is feasible for networked sensors. The aim of this work is to develop a method for the assembly of complete systems, consisting of a printed circuit board, components, and power supply, using a single production process. The first steps towards this aim have been taken, and the authors believe that the proposed approach may be one enabling technology for future large-scale, low-cost wireless sensor networks.
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| 12. |
- Kato, Norihiro, et al.
(författare)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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| 13. |
- Korinek, Michal, et al.
(författare)
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Anti-allergic Hydroxy Fatty Acids from Typhonium blumei Explored through ChemGPS-NP
- 2017
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Ingår i: Frontiers in Pharmacology. - : FRONTIERS MEDIA SA. - 1663-9812. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Increasing prevalence of allergic diseases with an inadequate variety of treatment drives forward search for new alternative drugs. Fatty acids, abundant in nature, are regarded as important bioactive compounds and powerful nutrients playing an important role in lipid homeostasis and inflammation. Phytochemical study on Typhonium blumei Nicolson and Sivadasan (Araceae), a folk anti-cancer and anti-inflammatory medicine, yielded four oxygenated fatty acids, 12R-hydroxyoctadec-9Z, 13E-dienoic acid methyl ester (1) and 10R-hydroxyoctadec-8E, 12Z-dienoic acid methyl ester (2), 9R-hydroxy-10E-octadecenoic acid methyl ester (3), and 12R *-hydroxy-10E-octadecenoic acid methyl ester (4). Isolated compounds were identified by spectroscopic methods along with GC-MS analysis. Isolated fatty acids together with a series of saturated, unsaturated and oxygenated fatty acids were evaluated for their anti-inflammatory and anti-allergic activities in vitro. Unsaturated (including docosahexaenoic and eicosapentaenoic acids) as well as hydroxylated unsaturated fatty acids exerted strong anti-inflammatory activity in superoxide anion generation (IC50 2.14-3.73 mu M) and elastase release (IC50 1.26-4.57 mu M) assays. On the other hand, in the anti-allergic assays, the unsaturated fatty acids were inactive, while hydroxylated fatty acids showed promising inhibitory activity in A23187-and antigen-induced degranulation assays (e.g., 9S-hydroxy-10E, 12Z-octadecadienoic acid, IC50 92.4 and 49.7 mu M, respectively). According to our results, the presence of a hydroxy group in the long chain did not influence the potent anti-inflammatory activity of free unsaturated acids. Nevertheless, hydroxylation of fatty acids (or their methyl esters) seems to be a key factor for the anti-allergic activity observed in the current study. Moreover, ChemGPS-NP was explored to predict the structure-activity relationship of fatty acids. The anti-allergic fatty acids formed different cluster distant from clinically used drugs. The bioactivity of T. blumei, which is historically utilized in folk medicine, might be related to the content of fatty acids and their metabolites.
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| 14. |
- Sung, Yun Ju, et al.
(författare)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 15. |
- Wang, Linqin, et al.
(författare)
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Design and synthesis of dopant-free organic hole-transport materials for perovskite solar cells
- 2018
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Ingår i: Chemical Communications. - : ROYAL SOC CHEMISTRY. - 1359-7345 .- 1364-548X. ; 54:69, s. 9571-9574
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Tidskriftsartikel (refereegranskat)abstract
- Two novel dopant-free hole-transport materials (HTMs) with spiro[dibenzo[c,h]xanthene-7,9-fluorene] (SDBXF) skeletons were prepared via facile synthesis routes. A power conversion efficiency of 15.9% in perovskite solar cells is attained by using one HTM without dopants, which is much higher than undoped Spiro-OMeTAD-based devices (10.8%). The crystal structures of both new HTMs were systematically investigated to reveal the reasons behind such differences in performance and to indicate the design principles of more advanced HTMs.
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| 16. |
- Wang, Yang, et al.
(författare)
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Role of point defects on the reactivity of reconstructed anatase titanium dioxide (001) surface
- 2013
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 2214-
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Tidskriftsartikel (refereegranskat)abstract
- The chemical reactivity of different surfaces of titanium dioxide (TiO2) has been the subject of extensive studies in recent decades. The anatase TiO2(001) and its (1 x 4) reconstructed surfaces were theoretically considered to be the most reactive and have been heavily pursued by synthetic chemists. However, the lack of direct experimental verification or determination of the active sites on these surfaces has caused controversy and debate. Here we report a systematic study on an anatase TiO2(001)-(1 x 4) surface by means of microscopic and spectroscopic techniques in combination with first-principles calculations. Two types of intrinsic point defects are identified, among which only the Ti3+ defect site on the reduced surface demonstrates considerable chemical activity. The perfect surface itself can be fully oxidized, but shows no obvious activity. Our findings suggest that the reactivity of the anatase TiO2(001) surface should depend on its reduction status, similar to that of rutile TiO2 surfaces.
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| 17. |
- Xiong, Dehua, et al.
(författare)
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Enhanced Performance of p-Type Dye-Sensitized Solar Cells Based on Ultrasmall Mg-Doped CuCrO2 Nanocrystals
- 2013
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Ingår i: ChemSusChem. - : Wiley. - 1864-5631 .- 1864-564X. ; 6:8, s. 1432-1437
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we present ultrasmall delafossite-type Mg-doped CuCrO2 nanocrystals prepared by using hydrothermal synthesis and their first application as photocathodes in efficient p-type dye-sensitized solar cells. The short-circuit current density (J(sc)) is notably increased by approximately 27% owing to the decreased crystallite size and the enhanced optical transmittance associated with Mg doping of the CuCrO2 nanocrystalline sample. An open-circuit voltage (V-oc) of 201mV, J(sc) of 1.51mAcm(-2), fill factor of 0.449, and overall photoconversion efficiency of 0.132% have been achieved with the CuCr0.9Mg0.1O2 dye photocathode sensitized with the P1 dye under optimized conditions. This efficiency is nearly threetimes higher than that of the NiO-based reference device, which is attributed to the largely improved V-oc and J(sc). The augmentation of V-oc and J(sc) can be attributed to the lower valance band position and the faster hole diffusion coefficient of CuCr0.9Mg0.1O2 compared to those of the NiO reference, respectively, which leads to a higher hole collection efficiency.
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| 18. |
- Zhang, Jinbao, et al.
(författare)
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Chemical Dopant Engineering in Hole Transport Layers for Efficient Perovskite Solar Cells : Insight into the Interfacial Recombination
- 2018
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 12:10, s. 10452-10462
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Tidskriftsartikel (refereegranskat)abstract
- Chemical doping of organic semiconductors has been recognized as an effective way to enhance the electrical conductivity. In perovskite solar cells (PSCs), various types of dopants have been developed for organic hole transport materials (HTMs); however, the knowledge of the basic requirements for being efficient dopants as well as the comprehensive roles of the dopants in PSCs has not been clearly revealed. Here, three copper-based complexes with controlled redox activities are applied as dopants in PSCs, and it is found that the oxidative reactivity of dopants presents substantial impacts on conductivity, charge dynamics, and solar cell performance. A significant improvement of open- circuit voltage (V-oc) by more than 100 mV and an increase of power conversion efficiency from 13.2 to 19.3% have been achieved by tuning the doping level of the HTM. The observed large variation of V-oc for three dopants reveals their different recombination kinetics at the perovskite/HTM interfaces and suggests a model of an interfacial recombination mechanism. We also suggest that the dopants in HTMs can also affect the charge recombination kinetics as well as the solar cell performance. Based on these findings, a strategy is proposed to physically passivate the electron- hole recombination by inserting an ultrathin Al2O3 insulating layer between the perovskite and the HTM. This strategy contributes a significant enhancement of the power conversion efficiency and environmental stability, indicating that dopant engineering is one crucial way to further improve the performance of PSCs.
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| 19. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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