1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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3. |
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4. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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5. |
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6. |
- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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7. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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8. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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10. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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11. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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12. |
- Abdo, A. A., et al.
(författare)
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The Fermi Gamma-Ray Space Telescope Discovers the Pulsar in the Young Galactic Supernova Remnant CTA 1
- 2008
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 322:5905, s. 1218-1221
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Tidskriftsartikel (refereegranskat)abstract
- Energetic young pulsars and expanding blast waves [ supernova remnants (SNRs)] are the most visible remains after massive stars, ending their lives, explode in core-collapse supernovae. The Fermi Gamma- Ray Space Telescope has unveiled a radio quiet pulsar located near the center of the compact synchrotron nebula inside the supernova remnant CTA 1. The pulsar, discovered through its gamma- ray pulsations, has a period of 316.86 milliseconds and a period derivative of 3.614 x 10(-13) seconds per second. Its characteristic age of 10(4) years is comparable to that estimated for the SNR. We speculate that most unidentified Galactic gamma- ray sources associated with star- forming regions and SNRs are such young pulsars.
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15. |
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16. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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17. |
- Abdo, A. A., et al.
(författare)
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FERMI DISCOVERY OF GAMMA-RAY EMISSION FROM NGC 1275
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 699:1, s. 31-39
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of high-energy (E > 100 MeV) gamma-ray emission from NGC 1275, a giant elliptical galaxy lying at the center of the Perseus cluster of galaxies, based on observations made with the Large Area Telescope (LAT) of the Fermi Gamma-ray Space Telescope. The positional center of the gamma-ray source is only approximate to 3' away from the NGC 1275 nucleus, well within the 95% LAT error circle of approximate to 5'. The spatial distribution of gamma-ay photons is consistent with a point source. The average flux and power-law photon index measured with the LAT from 2008 August 4 to 2008 December 5 are F-gamma = (2.10 +/- 0.23) x 10(-7) ph (>100 MeV) cm(-2) s(-1) and Gamma = 2.17 +/- 0.05, respectively. The measurements are statistically consistent with constant flux during the four-month LAT observing period. Previous EGRET observations gave an upper limit of F-gamma < 3.72 x 10(-8) ph (>100 MeV) cm(-2) s(-1) to the gamma-ray flux from NGC 1275. This indicates that the source is variable on timescales of years to decades, and therefore restricts the fraction of emission that can be produced in extended regions of the galaxy cluster. Contemporaneous and historical radio observations are also reported. The broadband spectrum of NGC 1275 is modeled with a simple one-zone synchrotron/synchrotron self-Compton model and a model with a decelerating jet flow.
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18. |
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19. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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20. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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21. |
- Abdo, A. A., et al.
(författare)
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DETECTION OF THE ENERGETIC PULSAR PSR B1509-58 AND ITS PULSAR WIND NEBULA IN MSH 15-52 USING THE FERMI-LARGE AREA TELESCOPE
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 714:1, s. 927-936
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Tidskriftsartikel (refereegranskat)abstract
- We report the detection of high-energy gamma-ray emission from the young and energetic pulsar PSR B1509-58 and its pulsar wind nebula (PWN) in the composite supernova remnant G320.4-1.2 (aka MSH 15-52). Using 1 yr of survey data with the Fermi-Large Area Telescope (LAT), we detected pulsations from PSR B1509-58 up to 1 GeV and extended gamma-ray emission above 1 GeV spatially coincident with the PWN. The pulsar light curve presents two peaks offset from the radio peak by phases 0.96 +/- 0.01 and 0.33 +/- 0.02. New constraining upper limits on the pulsar emission are derived below 1 GeV and confirm a severe spectral break at a few tens of MeV. The nebular spectrum in the 1-100 GeV energy range is well described by a power law with a spectral index of (1.57 +/- 0.17 +/- 0.13) and a flux above 1 GeV of (2.91 +/- 0.79 +/- 1.35) x 10(-9) cm(-2) s(-1). The first errors represent the statistical errors on the fit parameters, while the second ones are the systematic uncertainties. The LAT spectrum of the nebula connects nicely with Cherenkov observations, and indicates a spectral break between GeV and TeV energies.
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22. |
- Abdo, A. A., et al.
(författare)
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Fermi large area telescope observations of PSR J1836+5925
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 712:2, s. 1209-1218
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of the gamma-ray pulsar PSR J1836+5925, powering the formerly unidentified EGRET source 3EG J1835+5918, was one of the early accomplishments of the Fermi Large Area Telescope (LAT). Sitting 25 degrees off the Galactic plane, PSR J1836+5925 is a 173 ms pulsar with a characteristic age of 1.8 million years, a spindown luminosity of 1.1 x 10(34) erg s(-1), and a large off-peak (OP) emission component, making it quite unusual among the known gamma-ray pulsar population. We present an analysis of one year of LAT data, including an updated timing solution, detailed spectral results, and a long-term light curve showing no indication of variability. No evidence for a surrounding pulsar wind nebula is seen and the spectral characteristics of the OP emission indicate it is likely magnetospheric. Analysis of recent XMM-Newton observations of the X-ray counterpart yields a detailed characterization of its spectrum, which, like Geminga, is consistent with that of a neutron star showing evidence for both magnetospheric and thermal emission.
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28. |
- Isobe, T, et al.
(författare)
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Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4501-
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Tidskriftsartikel (refereegranskat)abstract
- KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
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29. |
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31. |
- Andersson, V., et al.
(författare)
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Large-Area Balloon-Borne Polarized Gamma Ray Observer (PoGO)
- 2005
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Ingår i: Proceedings of the 22nd Texas Symposium on Relativistic Astrophysics at Stanford. ; , s. 736-743
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Konferensbidrag (refereegranskat)abstract
- We are developing a new balloon-borne instrument (PoGO), to measure polarization of soft gamma rays (30-200 keV) using asymmetry in azimuth angle distribution of Compton scattering. PoGO is designed to detect 10 % polarization in 100mCrab sources in a 6-8 hour observation and bring a new dimension to studies on gamma ray emission/transportation mechanism in pulsars, AGNs, black hole binaries, and neutron star surface. The concept is an adaptation to polarization measurements of well-type phoswich counter consisting of a fast plastic scintillator (the detection part), a slow plastic scintillator (the active collimator) and a BGO scintillator (the bottom anti-counter). PoGO consists of close-packed array of 217 hexagonal well-type phoswich counters and has a narrow field-of-view (~ 5 deg2) to reduce possible source confusion. A prototype instrument has been tested in the polarized soft gamma-ray beams at Advanced Photon Source (ANL) and at Photon Factory (KEK). On the results, the polarization dependence of EGS4 has been validated and that of Geant4 has been corrected.
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32. |
- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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37. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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38. |
- Arimoto, M., et al.
(författare)
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Performance assessment study of the balloon-borne astronomical soft gamma-ray polarimeter PoGOLite
- 2007
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Ingår i: Physica. E, Low-Dimensional systems and nanostructures. - : Elsevier BV. - 1386-9477 .- 1873-1759. ; 40:2, s. 438-441
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of polarization play a crucial role in the understanding of the dominant emission mechanism of astronomical sources. Polarized Gamma-ray Observer-Light version (PoGOLite) is a balloon-borne astronomical soft gamma-ray polarimeter at the 25-80 keV band. The PoGOLite detector consists of a hexagonal close-packed array of 217 Phoswich detector cells (PDCs) and side anti-coincidence shields (SASs) made of BGO crystals surrounding PDCs. Each PDC consists of a slow hollow scintillator, a fast scintillator and a BGO crystal that connects to a photomultiplier tube at the end. To examine the PoGOLite's capability and estimate the performance, we conducted experiments with the PDC using radioisotope 241Am. In addition, we compared this result with performance expected by Monte Carlo simulation with Geant4. As a result, we found that the actual PDC has the capability to detect a 100 m Crab source until 80 keV.
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39. |
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40. |
- Kanai, Y., et al.
(författare)
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Beam test of a prototype phoswich detector assembly for the PoGOLite astronomical soft gamma-ray polarimeter
- 2007
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 570:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- We report about the beam test on a prototype of the balloon-based astronomical soft gamma-ray polarimeter, PoGOLite (Polarized Gamma-ray Observer-Light Version) conducted at KEK Photon Factory, a synchrotron radiation facility in Japan. The synchrotron beam was set at 30, 50, and 70 keV and its polarization was monitored by a calibrated polarimeter. The goal of the experiment was to validate the flight design of the polarimeter. PoGOLite is designed to measure polarization by detecting a Compton scattering and the subsequent photo-absorption in an array of 217 well-type phoswich detector cells (PDCs). The test setup included a first flight model PDC and a front-end electronics to select and reconstruct valid Compton scattering events. The experiment has verified that the flight PDC can detect recoil electrons and select valid Compton scattering events down to 30 keV from background. The measure azimuthal modulations (34.4%, 35.8% and 37.2% at 30, 50, and 70 keV, respectively) agreed within 10% (relative) with the predictions by Geant4 implemented with dependence on the initial and final photon polarizations.
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41. |
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42. |
- Mizuno, T., et al.
(författare)
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A Monte Carlo method for calculating the energy response of plastic scintillators to polarized photons below 100 keV
- 2009
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 600:3, s. 609-617
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Tidskriftsartikel (refereegranskat)abstract
- The energy response of plastic scintillators (Eljen Technology EJ-204) to polarized soft gamma-ray photons below 100 keV has been studied, primarily for the balloon-borne polarimeter, PoGOLite. The response calculation includes quenching effects due to low-energy recoil electrons and the position dependence of the light collection efficiency in a 20 cm long scintillator rod. The broadening of the pulse-height spectrum, presumably caused by light transportation processes inside the scintillator, as well as the generation and multiplication of photoelectrons in the photomultiplier tube, were studied experimentally and have also been taken into account. A Monte Carlo simulation based on the Geant4 toolkit was used to model photon interactions in the scintillators. When using the polarized Compton/Rayleigh scattering processes previously corrected by the authors, scintillator spectra and angular distributions of scattered polarized photons could clearly be reproduced, in agreement with the results obtained at a synchrotron beam test conducted at the KEK Photon Factory. Our simulation successfully reproduces the modulation factor, defined as the ratio of the amplitude to the mean of the distribution of the azimuthal scattering angles, within similar to 5% (relative). Although primarily developed for the PoGOLite mission, the method presented here is also relevant for other missions aiming to measure polarization from astronomical objects using plastic scintillator scatterers.
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43. |
- Pearce, Mark, et al.
(författare)
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PoGOLite : A balloon-borne soft gamma-ray polarimeter
- 2007
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Ingår i: Proceedings of the 30th International Cosmic Ray Conference, ICRC 2007. - : Universidad Nacional Autonoma de Mexico. ; , s. 479-482
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Konferensbidrag (refereegranskat)abstract
- Polarized gamma-rays are expected from a wide variety of sources including rotationpowered pulsars, accreting black holes and neutron stars, and jet-dominated active galaxies. Polarization measurements provide a powerful probe of the gamma-ray emission mechanism and the distribution of magnetic and radiation fields around the source. No measurements have been performed in the soft gamma-ray band where non-thermal processes are expected to produce high degrees of polarization. The PoGOLite experiment applies well-type phoswich detector technology to polarization measurements in the 25 - 80 keV energy range. The instrument uses Compton scattering and photoabsorption in an array of 217 phoswich detector cells made of plastic and BGO scintillators, and surrounded by active BGO shields. A prototype of the flight instrument has been tested with polarized gammarays and background generated with radioactive sources. The test results and computer simulations confirm that the instrument can detect 10% polarization of a 200 mCrab source in one 6 hour balloon observation. In flight, targets are constrained to within better than 5% of the field-of-view (~5 degrees squared) in order to maximize the effective detection area during observations. The pointing direction on the sky is determined by an attitude control system comprising star trackers, differential GPS receiver system, gyroscopes, accelerometers and magnetometers which provide correction signals to a reaction wheel and torque motor system. Additionally, the entire polarimeter assembly rotates around its viewing axis to minimize systematic bias during observations. Flights are foreseen to start in 2009- 2010 and will target northern sky sources including the Crab pulsar/nebula, Cygnus X-1, and Hercules X-1. These observations will provide valuable information about the pulsar emission mechanism, the geometry around the black hole, and photon transportation in the strongly magnetized neutron star surface, respectively. Future goals include a long duration balloon flight from the Esrange facility in Northern Sweden to Canada.
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44. |
- Tanaka, T., et al.
(författare)
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Data acquisition system for the PoGOLite astronomical hard X-ray polarimeter
- 2007
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Ingår i: Nuclear Science Symposium Conference Record, 2007. - 9781424409228 ; , s. 445-449, s. 445-449
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The PoGOLite is a new balloon-borne instrument to measure the polarization of hard X-rays/soft gamma-rays in the 25-80 keV energy range for the first time. In order to detect the polarization, PoGOLite measures the azimuthal angle asymmetry of Compton scattering and the subsequent photo-absorption in an array of detectors. This array consists of 217 well-type phoswich detector cells (PDCs) surrounded by a side anti-coincidence shield (SAS) composed of 54 segments of BGO crystals. At balloon altitude, the intensity of backgrounds due to cosmic-ray charged particles, atmospheric gamma-rays and neutrons is extremely high, typically a few hundred Hz per unit. Hence the data acquisition (DAQ) system of PoGOLite is required to handle more than 270 signals simultaneously, and detect weak signals from astrophysical objects (100mCrab, 1.5 cs(-1) in 25-80 keV) under such a severe environment. We have developed a new DAQ system consisting of front-end electronics, waveform digitizer, Field Programmable Gate Array (FPGA) and a microprocessor. In this system, all output signals of PDC / SAS are fed into individual charge-sensitive amplifier and then digitized to 12 bit accuracy at 24 MSa/s by pipelined analog to digital converters. A DAQ board for the PDC records waveforms which will be examined in an off-line analysis to distinguish signals from the background events and measure the energy spectrum and polarization of targets. A board for the SAS records hit pattern to be used for background rejection. It also continuously records a pulse-height analysis (PHA) histogram to monitor incident background flux. These basic functions of the DAQ system were verified in a series of beam tests.
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45. |
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46. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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47. |
- 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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48. |
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49. |
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50. |
- Mizuno, T., et al.
(författare)
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High sensitivity balloon-borne hard X-ray/soft Gamma-Ray Polarimeter PoGOLite
- 2007
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Ingår i: Nuclear Science Symposium Conference Record, 2007. NSS ’07. IEEE. - : IEEE. - 9781424409228 ; , s. 2538-2544
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Konferensbidrag (refereegranskat)abstract
- The Polarized Gamma-ray Observer - Lightweight version (PoGOLite) is a new balloon experiment capable of detecting 10% polarization from a 200 mCrab source in the 25-80 keV energy range in a single 6-hour flight for the first time. Polarization measurements of hard X-rays and soft gamma-rays are expected to provide a powerful probe into high-energy emission mechanisms as well as source geometries. PoGOLite uses Compton scattering and photo-absorption to measure polarization in an array of 217 well-type phoswich detector cells made of plastic and BGO scintillators. The adoption of a well-type phoswich counter concept and a thick polyethylene neutron shield provides a narrow field-of-view (1.25 msr), a large effective area ( gt; 250 cm2 at 40-50 keV), a high modulation factor (more than 25%) and the low background ( 100 mCrab) required to conduct high-sensitivity polarization measurements. Through tests in laboratories and accelerator facilities of a scaled-down prototype with the front-end electronics of flight design and an extensive study by Monte Carlo simulation, we have demonstrated high instrument performance. PoGOLite will be ready for a first engineering flight in 2009 and a science flight in 2010, during which polarization signals from the Crab Nebula/pulsar, Cygnus X-1 and other objects will be observed.
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