| 1. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 2. |
- Zhou, Wei, et al.
(författare)
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Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
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Ingår i: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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| 3. |
- Kato, Yuta, et al.
(författare)
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A high dust emissivity index beta for a CO-faint galaxy in a filamentary Ly alpha nebula at z=3.1
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:5
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Tidskriftsartikel (refereegranskat)abstract
- We present CO J = 4-3 line and 3 mm dust continuum observations of a 100 kpc-scale filamentary Ly alpha nebula (SSA22 LAB18) at z = 3.1 using the Atacama Large Millimeter/submillimeter Array (ALMA). We detected the CO J = 4-3 line at a systemic z(CO) = 3.093 +/- 0.001 at 11 sigma from one of the ALMA continuum sources associated with the Ly alpha filament. We estimated the CO J = 4-3 luminosity of L'(CO(4-3)) = (2.3 +/- 0.2) x 10(9) Kkms(-1) pc(2) for this CO source, which is one order of magnitude smaller than those of typical z > 1 dusty star-forming galaxies (DSFGs) of similar far-infrared luminosity L-IR similar to 10(12) L-circle dot. We derived a molecular gas mass of M-gas = (4.4(-0.6)(+0.9)) x 10(9) M-circle dot and a star-formation rate of SFR = 270 +/- 160M(circle dot) yr(-1). We also estimated a gas depletion time of tau(dep) = 17 +/- 10 Myr, which is shorter than those of typical DSFGs. It is suggested that this source is in the transition phase from DSFG to a gas-poor, early-type galaxy. From ALMA to Herschel multi-band dust continuum observations, we measured a dust emissivity index beta = 2.3 +/- 0.2, which is similar to those of local gas-poor, early-type galaxies. From recent laboratory experiments, the specific chemical compositions needed to reproduce such a high beta for interstellar dust at the submillimeter wavelengths. ALMA CO and multi-band dust continuum observations can constrain the evolutionary stage of high-redshift galaxies through tau(dep) and beta, and thus we can investigate the chemical composition of dust even in the early Universe.
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| 4. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 5. |
- Umehata, Hideki, et al.
(författare)
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ALMA Reveals Strong [C II] Emission in a Galaxy Embedded in a Giant Ly alpha Blob at z=3.1
- 2017
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 834:2
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Tidskriftsartikel (refereegranskat)abstract
- We report the result from observations conducted with the Atacama Large Millimeter/submillimeter Array (ALMA) to detect [C II] 158 mu m fine structure line emission from galaxies embedded in one of the most spectacular Ly alpha blobs (LABs) at z = 3.1, SSA22-LAB1. Of three dusty star-forming galaxies previously discovered by ALMA 860 mu m dust continuum survey toward SSA22-LAB1, we detected the [C II] line from one, LAB1-ALMA3 at z = 3.0993 +/- 0.0004. No line emission was detected, associated with the other ALMA continuum sources or from three rest-frame UV/optical selected z(spec) similar or equal to 3.1 galaxies within the field of view. For LAB1-ALMA3, we find relatively bright [C II] emission compared to the infrared luminosity (L-[C II]/LIR approximate to 0.01) and an extremely high [C II] 158 mu m and [N II] 205 mu m emission line ratio (L[C II]/L[N II] > 55). The relatively strong [C II] emission may be caused by abundant photodissociation regions and sub-solar metallicity, or by shock heating. The origin of the unusually strong [C II] emission could be causally related to the location within the giant LAB, although the relationship between extended Ly alpha emission and interstellar medium conditions of associated galaxies is yet to be understand.
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