Papers - Ishigaki, Kazuyoshi

Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

 2021.12

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Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy.

Taniguchi-Ikeda M, Koyanagi-Aoi M, Maruyama T, Takaori T, Hosoya A, Tezuka H, Nagase S, Ishihara T, Kadoshima T, Muguruma K, Ishigaki K, Sakurai H, Mizoguchi A, Novitch BG, Toda T, Watanabe M, Aoi T

iScience 24 ( 10 ) 103140 2021.10

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A cross-population atlas of genetic associations for 220 human phenotypes

Sakaue S., Kanai M., Tanigawa Y., Karjalainen J., Kurki M., Koshiba S., Narita A., Konuma T., Yamamoto K., Akiyama M., Ishigaki K., Suzuki A., Suzuki K., Obara W., Yamaji K., Takahashi K., Asai S., Takahashi Y., Suzuki T., Shinozaki N., Yamaguchi H., Minami S., Murayama S., Yoshimori K., Nagayama S., Obata D., Higashiyama M., Masumoto A., Koretsune Y., Ito K., Terao C., Yamauchi T., Komuro I., Kadowaki T., Tamiya G., Yamamoto M., Nakamura Y., Kubo M., Murakami Y., Yamamoto K., Kamatani Y., Palotie A., Rivas M.A., Daly M.J., Matsuda K., Okada Y.

Nature Genetics 53 ( 10 ) 1415 - 1424 2021.10

ISSN  10614036

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Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n<inf>total</inf> = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

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Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism.

Sano M, Takahashi R, Ijichi H, Ishigaki K, Yamada T, Miyabayashi K, Kimura G, Mizuno S, Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim J, Masugi Y, Morishita Y, Tanaka M, Ushiku T, Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses HL, Koike K

Gut 70 ( 9 ) 1713 - 1723 2021.09

ISSN  0017-5749

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Modeling memory T cell states at single-cell resolution identifies in vivo state-dependence of eQTLs influencing disease

Aparna Nathan and Samira Asgari and Kazuyoshi Ishigaki and Tiffany Amariuta and Yang Luo and Jessica I Beynor and Yuriy Baglaenko and Sara Suliman and Alkes Price and Leonid Lecca and Megan B Murray and D. Branch Moody and Soumya Raychaudhuri

(Cold Spring Harbor Laboratory)   2021.07

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Contribution of a European-Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome-Wide Association Study Meta-Analyses

Bing N., Zhou H., Chen X., Hirose T., Kochi Y., Tsuchida Y., Ishigaki K., Sumitomo S., Fujio K., Zhang B., Valdez H., Vincent M.S., Martin D., Clark J.D.

Arthritis and Rheumatology 73 ( 7 ) 1155 - 1166 2021.07

ISSN  23265191

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Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. Methods: In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. Results: In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10⁻⁸), including a single-nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans-ethnic, trans-population meta-analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta-analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta-analysis hazard ratio 3.6 [95% confidence interval 2.40–5.44], P = 7.6 × 10⁻¹⁰; frequency of risk allele ~12% in East Asian subjects versus <0.2% in European subjects). Conclusion: Genetic analysis of tofacitinib-treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune-relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib-treated subjects.

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Repertoire analyses reveal TCR sequence features that influence T cell fate

Kaitlyn A. Lagattuta and Joyce B. Kang and Aparna Nathan and Kristen E. Pauken and Anna Helena Jonsson and Deepak A. Rao and Kazuyoshi Ishigaki and Soumya Raychaudhuri

(Cold Spring Harbor Laboratory)   2021.06

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Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease

Nathan A., Beynor J.I., Baglaenko Y., Suliman S., Ishigaki K., Asgari S., Huang C.C., Luo Y., Zhang Z., Lopez K., Lindestam Arlehamn C.S., Ernst J.D., Jimenez J., Calderón R.I., Lecca L., Van Rhijn I., Moody D.B., Murray M.B., Raychaudhuri S.

Nature Immunology (Springer Science and Business Media {LLC})  22 ( 6 ) 781 - 793 2021.06

ISSN  15292908

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Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (T<inf>H</inf>17) cell–like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.tb) infection to active TB disease. These cells are capable of responding to M.tb peptides. Deconvoluting this state—uniquely identifiable with multimodal analysis—from public data demonstrated that its depletion may precede and persist beyond active disease. Our study demonstrates the power of integrative multimodal single-cell profiling to define cell states relevant to disease and other traits.

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Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Ota M., Nagafuchi Y., Hatano H., Ishigaki K., Terao C., Takeshima Y., Yanaoka H., Kobayashi S., Okubo M., Shirai H., Sugimori Y., Maeda J., Nakano M., Yamada S., Yoshida R., Tsuchiya H., Tsuchida Y., Akizuki S., Yoshifuji H., Ohmura K., Mimori T., Yoshida K., Kurosaka D., Okada M., Setoguchi K., Kaneko H., Ban N., Yabuki N., Matsuki K., Mutoh H., Oyama S., Okazaki M., Tsunoda H., Iwasaki Y., Sumitomo S., Shoda H., Kochi Y., Okada Y., Yamamoto K., Okamura T., Fujio K.

Cell 184 ( 11 ) 3006 - 3021.e17 2021.05

ISSN  00928674

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Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

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Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus

Yin X., Kim K., Suetsugu H., Bang S.Y., Wen L., Koido M., Ha E., Liu L., Sakamoto Y., Jo S., Leng R.X., Otomo N., Laurynenka V., Kwon Y.C., Sheng Y., Sugano N., Hwang M.Y., Li W., Mukai M., Yoon K., Cai M., Ishigaki K., Chung W.T., Huang H., Takahashi D., Lee S.S., Wang M., Karino K., Shim S.C., Zheng X., Miyamura T., Kang Y.M., Ye D., Nakamura J., Suh C.H., Tang Y., Motomura G., Park Y.B., Ding H., Kuroda T., Choe J.Y., Li C., Niiro H., Park Y., Shen C., Miyamoto T., Ahn G.Y., Fei W., Takeuchi T., Shin J.M., Li K., Kawaguchi Y., Lee Y.K., Wang Y., Amano K., Park D.J., Yang W., Tada Y., Yamaji K., Shimizu M., Atsumi T., Suzuki A., Sumida T., Okada Y., Matsuda K., Matsuo K., Kochi Y., Kottyan L.C., Weirauch M.T., Parameswaran S., Eswar S., Salim H., Chen X., Yamamoto K., Harley J.B., Ohmura K., Kim T.H., Yang S., Yamamoto T., Kim B.J., Shen N., Ikegawa S., Lee H.S., Zhang X., Terao C., Cui Y., Bae S.C.

Annals of the Rheumatic Diseases 80 ( 5 ) 632 - 640 2021.05

ISSN  00034967

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Objective Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated withnearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. Methods We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. Results We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10 -8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r g =-0.242) and non-albumin protein (r g =0.238). Conclusion Thisstudy reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

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Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Tsuchiya H., Ota M., Sumitomo S., Ishigaki K., Suzuki A., Sakata T., Tsuchida Y., Inui H., Hirose J., Kochi Y., Kadono Y., Shirahige K., Tanaka S., Yamamoto K., Fujio K.

Annals of the Rheumatic Diseases 80 ( 4 ) 440 - 450 2021.04

ISSN  00034967

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Objectives Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition. Methods SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN- γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-6/sIL-6R, IL-17, transforming growth factor-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4 + T cells, CD8 + T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed. Results Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including CD40 whose induction by IFN-γwas significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of metal-regulatory transcription factor-1 (MTF1) gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis. Conclusions Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.

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