| 1. |
- Ramdas, S., et al.
(author)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Journal article (peer-reviewed)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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| 2. |
- Sugai, H., et al.
(author)
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Updated Design of the CMB Polarization Experiment Satellite LiteBIRD
- 2020
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In: Journal of Low Temperature Physics. - : Springer Science and Business Media LLC. - 0022-2291 .- 1573-7357. ; 199:3-4, s. 1107-1117
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Journal article (peer-reviewed)abstract
- Recent developments of transition-edge sensors (TESs), based on extensive experience in ground-based experiments, have been making the sensor techniques mature enough for their application on future satellite cosmic microwave background (CMB) polarization experiments. LiteBIRD is in the most advanced phase among such future satellites, targeting its launch in Japanese Fiscal Year 2027 (2027FY) with JAXA's H3 rocket. It will accommodate more than 4000 TESs in focal planes of reflective low-frequency and refractive medium-and-high-frequency telescopes in order to detect a signature imprinted on the CMB by the primordial gravitational waves predicted in cosmic inflation. The total wide frequency coverage between 34 and 448 GHz enables us to extract such weak spiral polarization patterns through the precise subtraction of our Galaxy's foreground emission by using spectral differences among CMB and foreground signals. Telescopes are cooled down to 5 K for suppressing thermal noise and contain polarization modulators with transmissive half-wave plates at individual apertures for separating sky polarization signals from artificial polarization and for mitigating from instrumental 1/f noise. Passive cooling by using V-grooves supports active cooling with mechanical coolers as well as adiabatic demagnetization refrigerators. Sky observations from the second Sun-Earth Lagrangian point, L2, are planned for 3 years. An international collaboration between Japan, the USA, Canada, and Europe is sharing various roles. In May 2019, the Institute of Space and Astronautical Science, JAXA, selected LiteBIRD as the strategic large mission No. 2.
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| 8. |
- Bakker, M. K., et al.
(author)
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Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
- 2020
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:12, s. 1303-1313
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Journal article (peer-reviewed)abstract
- Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.
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| 9. |
- Ramilowski, JA, et al.
(author)
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Functional annotation of human long noncoding RNAs via molecular phenotyping
- 2020
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In: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:7, s. 1060-1072
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Journal article (peer-reviewed)abstract
- Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
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| 13. |
- Ejiri, M.K., et al.
(author)
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Validation of the Improved Limb Atmospheric Spectrometer-II (ILAS-II) Version 1.4 nitrous oxide and methane profiles
- 2006
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In: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 111:D22
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Journal article (peer-reviewed)abstract
- This study assesses polar stratospheric nitrous oxide (N(2)O) and methane (CH(4)) data from the Improved Limb Atmospheric Spectrometer-II (ILAS-II) on board the Advanced Earth Observing Satellite-II (ADEOS-II) retrieved by the Version 1.4 retrieval algorithm. The data were measured between January and October 2003. Vertical profiles of ILAS-II volume mixing ratio (VMR) data are compared with data from two balloon-borne instruments, the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS-B) and the MkIV instrument, as well as with two satellite sensors, the Odin Sub-Millimetre Radiometer (SMR) for N(2)O and the Halogen Occultation Experiment (HALOE) for CH(4). Relative percentage differences between the ILAS-II and balloon/satellite data and their median values are calculated in 10-ppbv-wide bins for N(2)O (from 0 to 400 ppbv) and in 0.05-ppmv-wide bins for CH(4) (from 0 to 2 ppmv) in order to assess systematic differences between the ILAS-II and balloon/satellite data. According to this study, the characteristics of the ILAS-II Version 1.4 N(2)O and CH(4) data differ between hemispheres. For ILAS-II N(2)O VMR larger than 250 ppbv, the ILAS-II N(2)O agrees with the balloon/SMR N(2)O within +/- 20% in both hemispheres. The ILAS-II N(2)O in the VMR range from 30-50 to 250 ppbv (corresponding to altitudes of similar to 17-30 km in the Northern Hemisphere (NH, mainly outside the polar vortex) and similar to 13-21 km in the Southern Hemisphere (SH, mainly inside the polar vortex) is smaller by similar to 10-30% than the balloon/SMR N(2)O. For ILAS-II N(2)O VMR smaller than 30 ppbv (>similar to 21 km) in the SH, the differences between the ILAS-II and SMR N(2)O are within +/- 10 ppbv. For ILAS-II CH(4) VMR larger than 1 ppmv (similar to 30 km) and the ILAS-II CH(4) for its VMR smaller than 1 ppmv (>similar to 25 km) only in the NH, are abnormally small compared to the balloon/satellite data.
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| 17. |
- Jaworek, T., et al.
(author)
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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
- 2022
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In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16
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Journal article (peer-reviewed)abstract
- Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
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| 18. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)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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| 19. |
- Mullins, N., et al.
(author)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 20. |
- Noboriguchi, Akatoki, et al.
(author)
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Extreme Nature of Four Blue-excess Dust-obscured Galaxies Revealed by Optical Spectroscopy
- 2022
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 941:2
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Journal article (peer-reviewed)abstract
- We report optical spectroscopic observations of four blue-excess dust-obscured galaxies (BluDOGs) identified by the Subaru Hyper Suprime-Cam. BluDOGs are a subclass of dust-obscured galaxies (DOGs; defined with the extremely red color (i − [22])AB ≥ 7.0; Toba et al., showing a significant flux excess in the optical g and r bands over the power-law fits to the fluxes at the longer wavelengths. Noboriguchi et al. have suggested that BluDOGs may correspond to the blowing-out phase involved in a gas-rich major-merger scenario. However, the detailed properties of BluDOGs are not understood because of the lack of spectroscopic information. In this work, we carry out deep optical spectroscopic observations of four BluDOGs using Subaru/FOCAS and VLT/FORS2. The obtained spectra show broad emission lines with extremely large equivalent widths, and a blue wing in the C iv line profile. The redshifts are between 2.2 and 3.3. The averaged rest-frame equivalent widths of the C iv lines are 160 ± 33 Å, ∼7 times higher than the average of a typical type 1 quasar. The FWHMs of their velocity profiles are between 1990 and 4470 km s−1, and their asymmetric parameters are 0.05 and 0.25. Such strong C iv lines significantly affect the broadband magnitudes, which are partly the origin of the blue excess seen in the spectral energy distribution of BluDOGs. Their estimated supermassive black hole masses are 1.1 × 108 < M BH/M ⊙ <5.5 × 108. The inferred Eddington ratios of the BluDOGs are higher than 1 (1.1 < λ Edd < 3.8), suggesting that the BluDOGs are in a rapidly evolving phase of supermassive black holes.
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| 22. |
- Wang, Anqi, et al.
(author)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Journal article (peer-reviewed)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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