Details of a Researcher - Ishigaki, Kazuyoshi

Papers - Ishigaki, Kazuyoshi

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Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy

Akiyama M., Miyake M., Momozawa Y., Arakawa S., Maruyama-Inoue M., Endo M., Iwasaki Y., Ishigaki K., Matoba N., Okada Y., Yasuda M., Oshima Y., Yoshida S., Nakao S.y., Morino K., Mori Y., Kido A., Kato A., Yasukawa T., Obata R., Nagai Y., Takahashi K., Fujisawa K., Miki A., Nakamura M., Honda S., Ushida H., Yasuma T., Nishiguchi K.M., Mori R., Tanaka K., Wakatsuki Y., Yamashiro K., Kadonosono K., Terao C., Ishibashi T., Tsujikawa A., Sonoda K.H., Kubo M., Kamatani Y.

Ophthalmology 130 ( 4 ) 361 - 372 2023.04

ISSN 01616420

Purpose: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. Design: Genome-wide association study (GWAS). Participants: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. Methods: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. Main Outcome Measures: Associations of genetic variants with AMD. Results: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10–8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10–12 and P = 1.35 × 10–9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10–3 and P = 4.28 × 10–3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (r<inf>g</inf> [the measure of genetic correlation] = –0.33; P = 0.01; false discovery rate, 0.099). Conclusions: Our findings imply shared genetic components conferring the risk of both AMD and CSC. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

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Functional Genetics to Understand the Etiology of Autoimmunity

Hatano H., Ishigaki K.

Genes 14 ( 3 ) 2023.03

Common variants strongly influence the risk of human autoimmunity. Two categories of variants contribute substantially to the risk: (i) coding variants of HLA genes and (ii) non-coding variants at the non-HLA loci. We recently developed a novel analytic pipeline of T cell receptor (TCR) repertoire to understand how HLA coding variants influence the risk. We identified that the risk variants increase the frequency of auto-reactive T cells. In addition, to understand how non-coding variants contribute to the risk, the researchers conducted integrative analyses using expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) and demonstrated that the risk non-coding variants dysregulate specific genes’ expression and splicing. These studies provided novel insight into the immunological consequences of two major genetic risks, and we will introduce these research achievements in detail in this review.

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T CELL RECEPTOR-MEDIATED REGULATION OF IMMUNE SYSTEM

Ishigaki K.

Japanese Journal of Allergology 72 ( 8 ) 1021 - 1025 2023

ISSN 00214884

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Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci

Yamaguchi K., Ishigaki K., Suzuki A., Tsuchida Y., Tsuchiya H., Sumitomo S., Nagafuchi Y., Miya F., Tsunoda T., Shoda H., Fujio K., Yamamoto K., Kochi Y.

Nature Communications 13 ( 1 ) 4659 2022.12

Splicing quantitative trait loci (sQTLs) are one of the major causal mechanisms in genome-wide association study (GWAS) loci, but their role in disease pathogenesis is poorly understood. One reason is the complexity of alternative splicing events producing many unknown isoforms. Here, we propose two approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms. First, we integrate isoforms with the same coding sequence (CDS) and identify 369-601 integrated-isoform ratio QTLs (i2-rQTLs), which altered protein-structure, in six immune subsets. Second, we select CDS incomplete isoforms annotated in GENCODE and identify 175-337 isoform-ratio QTL (i-rQTL). By comprehensive long-read capture RNA-sequencing among these incomplete isoforms, we reveal 29 full-length isoforms with unannotated CDSs associated with GWAS traits. Furthermore, we show that disease-causal sQTL genes can be identified by evaluating their trans-eQTL effects. Our approaches highlight the understudied role of protein-altering sQTLs and are broadly applicable to other tissues and diseases.

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Control of naive and effector CD4 T cell receptor repertoires by rheumatoid-arthritis-risk HLA alleles

Nagafuchi Y., Ota M., Hatano H., Inoue M., Kobayashi S., Okubo M., Sugimori Y., Nakano M., Yamada S., Yoshida R., Tsuchida Y., Iwasaki Y., Shoda H., Okada Y., Yamamoto K., Ishigaki K., Okamura T., Fujio K.

Journal of Autoimmunity 133 102907 2022.12

ISSN 08968411

Objective: Human Leukocyte Antigen (HLA) alleles regulate susceptibility to rheumatoid arthritis (RA) and immune-mediated diseases. This study aims to elucidate the impact of HLA alleles to T cell subsets. Methods: We performed genome-wide and HLA allele association analysis for T cell receptor (TCR) beta chain repertoire in 13 purified T cell subsets from the ImmuNexUT database, consisting of 407 donors with ten immune-mediated diseases and healthy controls. Results: HLA class II alleles were associated with TRBV gene usage and the public clones of CD4 T cells, while HLA class I alleles were associated with CD8 T cells. RA-risk and immune-mediated diseases-risk HLA alleles were associated with TRBV gene usage of naive and effector CD4 T cell subsets and public clones accumulating in Th17. Clonal diversity was independent of HLA alleles and was correlated with transcriptome changes that reflect TCR signaling. Conclusion: This study revealed in vivo evidence that both HLA alleles and environmental factors shape naive and effector TCR repertoires in RA and immune-mediated diseases patients.

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Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

Sakamoto M, Iwama K, Sasaki M, Ishiyama A, Komaki H, Saito T, Takeshita E, Shimizu-Motohashi Y, Haginoya K, Kobayashi T, Goto T, Tsuyusaki Y, Iai M, Kurosawa K, Osaka H, Tohyama J, Kobayashi Y, Okamoto N, Suzuki Y, Kumada S, Inoue K, Mashimo H, Arisaka A, Kuki I, Saijo H, Yokochi K, Kato M, Inaba Y, Gomi Y, Saitoh S, Shirai K, Morimoto M, Izumi Y, Watanabe Y, Nagamitsu SI, Sakai Y, Fukumura S, Muramatsu K, Ogata T, Yamada K, Ishigaki K, Hirasawa K, Shimoda K, Akasaka M, Kohashi K, Sakakibara T, Ikuno M, Sugino N, Yonekawa T, Gürsoy S, Cinleti T, Kim CA, Teik KW, Yan CM, Haniffa M, Ohba C, Ito S, Saitsu H, Saida K, Tsuchida N, Uchiyama Y, Koshimizu E, Fujita A, Hamanaka K, Misawa K, Miyatake S, Mizuguchi T, Miyake N, Matsumoto N

Genetics in medicine : official journal of the American College of Medical Genetics 24 ( 12 ) 2453 - 2463 2022.12

ISSN 1098-3600

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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Aragam K.G., Jiang T., Goel A., Kanoni S., Wolford B.N., Atri D.S., Weeks E.M., Wang M., Hindy G., Zhou W., Grace C., Roselli C., Marston N.A., Kamanu F.K., Surakka I., Venegas L.M., Sherliker P., Koyama S., Ishigaki K., Åsvold B.O., Brown M.R., Brumpton B., de Vries P.S., Giannakopoulou O., Giardoglou P., Gudbjartsson D.F., Güldener U., Haider S.M.I., Helgadottir A., Ibrahim M., Kastrati A., Kessler T., Kyriakou T., Konopka T., Li L., Ma L., Meitinger T., Mucha S., Munz M., Murgia F., Nielsen J.B., Nöthen M.M., Pang S., Reinberger T., Schnitzler G., Smedley D., Thorleifsson G., von Scheidt M., Ulirsch J.C., Danesh J., Arnar D.O., Burtt N.P., Costanzo M.C., Flannick J., Ito K., Jang D.K., Kamatani Y., Khera A.V., Komuro I., Kullo I.J., Lotta L.A., Nelson C.P., Roberts R., Thorgeirsson G., Thorsteinsdottir U., Webb T.R., Baras A., Björkegren J.L.M., Boerwinkle E., Dedoussis G., Holm H., Hveem K., Melander O., Morrison A.C., Orho-Melander M., Rallidis L.S., Ruusalepp A., Sabatine M.S., Stefansson K., Zalloua P., Ellinor P.T., Farrall M., Ruff C.T., Finucane H.K., Hopewell J.C., Clarke R., Gupta R.M., Erdmann J., Samani N.J., Schunkert H., Watkins H., Willer C.J., Deloukas P., Kathiresan S., Butterworth A.S., de Vries P.S.

Nature Genetics 54 ( 12 ) 1803 - 1815 2022.12

ISSN 10614036

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

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High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the Accelerating Medicines Partnership

Carlucci P.M., Li J., Fava A., Deonaraine K.K., Wofsy D., James J.A., Putterman C., Diamond B., Davidson A., Fine D.M., Monroy-Trujillo J., Atta M.G., Dejager W., Guthridge J.M., Haag K., Rao D.A., Brenner M.B., Lederer J.A., Apruzzese W., Belmont H.M., Izmirly P.M., Zaminski D., Wu M., Connery S., Payan-Schober F., Furie R., Dall'era M., Cho K., Kamen D., Kalunian K., Anolik J., Barnas J., Ishimori M., Weisman M.H., Goff J., Dunn P.J., Raychaudhuri S., Zhang F., Korsunsky I., Nathan A., Mears J., Ishigaki K., Xiao Q., Millard N., Weinand K., Sakaue S., Utz P.J., Mao R., Robinson B., Maecker H., MacWana S., Bridges S.L., Bykerk V., Donlin L., Goodman S., Dicarlo E., Smith M., Lakhanpal A., Sherman H., Singaraju A., Shakib L., Ritchlin C., Boyce B., Tabechian D., McDavid A., Rangel-Moreno J., Meednu N., Albrecht J., Wei K., Helena Jonsson A., Simmons D., Keras G., Keegan J., Watts G., Li Zhu Y., Chicoine A., Jian Li Z., Gravallese E.M., Howard K., McGeachy M., Firestein G.S., Boyle D.L., Ceponis A., Gregersen P.K., Horowitz D., Perlman H., Dominguez S., Cuda C.M., Mandolin A.M., Thakrar A., Bathon J.M., Hughes L., Michael Holers V., Seifert J., Deane K., Moreland L.W., Filer A., Raza K., Sahbudin I., Pitzalis C.

Rheumatology United Kingdom 61 ( 11 ) 4335 - 4343 2022.11

ISSN 14620324

Objective: Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. Methods: A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. Results: At biopsy, 54 patients had UPCR <1 and 221 had UPCR ≥1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at 1 year. Conclusion: In this prospective study, three-quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.

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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Ishigaki K., Sakaue S., Terao C., Luo Y., Sonehara K., Yamaguchi K., Amariuta T., Too C.L., Laufer V.A., Scott I.C., Viatte S., Takahashi M., Ohmura K., Murasawa A., Hashimoto M., Ito H., Hammoudeh M., Emadi S.A., Masri B.K., Halabi H., Badsha H., Uthman I.W., Wu X., Lin L., Li T., Plant D., Barton A., Orozco G., Verstappen S.M.M., Bowes J., MacGregor A.J., Honda S., Koido M., Tomizuka K., Kamatani Y., Tanaka H., Tanaka E., Suzuki A., Maeda Y., Yamamoto K., Miyawaki S., Xie G., Zhang J., Amos C.I., Keystone E., Wolbink G., van der Horst-Bruinsma I., Cui J., Liao K.P., Carroll R.J., Lee H.S., Bang S.Y., Siminovitch K.A., de Vries N., Alfredsson L., Rantapää-Dahlqvist S., Karlson E.W., Bae S.C., Kimberly R.P., Edberg J.C., Mariette X., Huizinga T., Dieudé P., Schneider M., Kerick M., Denny J.C., Matsuda K., Matsuo K., Mimori T., Matsuda F., Fujio K., Tanaka Y., Kumanogoh A., Traylor M., Lewis C.M., Eyre S., Xu H., Saxena R., Arayssi T., Kochi Y., Ikari K., Harigai M., Gregersen P.K., Yamamoto K., Louis Bridges S., Padyukov L., Martin J., Klareskog L., Okada Y., Raychaudhuri S.

Nature Genetics 54 ( 11 ) 1640 - 1651 2022.11

ISSN 10614036

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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Immunosuppression causes dynamic changes in expression QTLs in psoriatic skin

2022.10

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Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

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., 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.F., Amano K., Park D.J., Yang W., Tada Y., Lau Y.L., Yamaji K., Zhu Z., Shimizu M., Atsumi T., Suzuki A., Sumida T., Okada Y., Matsuda K., Matsuo K., Kochi Y., Yamamoto K., 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 81 ( 9 ) 1273 - 1280 2022.09

ISSN 00034967

Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0×10 -5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10 -8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 -9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

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Distinct transcriptome architectures underlying lupus establishment and exacerbation

Nakano M., Ota M., Takeshima Y., Iwasaki Y., Hatano H., Nagafuchi Y., Itamiya T., Maeda J., Yoshida R., Yamada S., Nishiwaki A., Takahashi H., Takahashi H., Akutsu Y., Kusuda T., Suetsugu H., Liu L., Kim K., Yin X., Bang S.Y., Cui Y., Lee H.S., Shoda H., Zhang X., Bae S.C., Terao C., Yamamoto K., Okamura T., Ishigaki K., Fujio K.

Cell 185 ( 18 ) 3375 - 3389.e21 2022.09

ISSN 00928674

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregulated gene expression pattern linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We then identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and therapeutic responses. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that current genetic studies may not well capture clinically vital biology. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic and genetic studies.

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Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

Tcheandjieu C., Zhu X., Hilliard A.T., Clarke S.L., Napolioni V., Ma S., Lee K.M., Fang H., Chen F., Lu Y., Tsao N.L., Raghavan S., Koyama S., Gorman B.R., Vujkovic M., Klarin D., Levin M.G., Sinnott-Armstrong N., Wojcik G.L., Plomondon M.E., Maddox T.M., Waldo S.W., Bick A.G., Pyarajan S., Huang J., Song R., Ho Y.L., Buyske S., Kooperberg C., Haessler J., Loos R.J.F., Do R., Verbanck M., Chaudhary K., North K.E., Avery C.L., Graff M., Haiman C.A., Le Marchand L., Wilkens L.R., Bis J.C., Leonard H., Shen B., Lange L.A., Giri A., Dikilitas O., Kullo I.J., Stanaway I.B., Jarvik G.P., Gordon A.S., Hebbring S., Namjou B., Kaufman K.M., Ito K., Ishigaki K., Kamatani Y., Verma S.S., Ritchie M.D., Kember R.L., Baras A., Lotta L.A., Kathiresan S., Hauser E.R., Miller D.R., Lee J.S., Saleheen D., Reaven P.D., Cho K., Gaziano J.M., Natarajan P., Huffman J.E., Voight B.F., Rader D.J., Chang K.M., Lynch J.A., Damrauer S.M., Wilson P.W.F., Tang H., Sun Y.V., Tsao P.S., O’Donnell C.J., Assimes T.L.

Nature Medicine 28 ( 8 ) 1679 - 1692 2022.08

ISSN 10788956

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

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Single-cell eQTL models reveal dynamic T cell state dependence of disease loci

Nathan A., Asgari S., Ishigaki K., Valencia C., Amariuta T., Luo Y., Beynor J.I., Baglaenko Y., Suliman S., Price A.L., Lecca L., Murray M.B., Moody D.B., Raychaudhuri S.

Nature 606 ( 7912 ) 120 - 128 2022.06

ISSN 00280836

Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by differences in gene regulation across fluid functional cell states within cell types. These states—for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation—are obscured in eQTL studies that aggregate cells1,2. Here we modelled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using more than 500,000 unstimulated memory T cells from 259 Peruvian individuals, we show that around one-third of 6,511 cis-eQTLs had effects that were mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, independent eQTL variants had opposing cell-state relationships. Autoimmune variants were enriched in cell-state-dependent eQTLs, including risk variants for rheumatoid arthritis near ORMDL3 and CTLA4; this indicates that cell-state context is crucial to understanding potential eQTL pathogenicity. Moreover, continuous cell states explained more variation in eQTLs than did conventional discrete categories, such as CD4+ versus CD8+, suggesting that modelling eQTLs and cell states at single-cell resolution can expand insight into gene regulation in functionally heterogeneous cell types.

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Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus

Takeshima Y., Iwasaki Y., Nakano M., Narushima Y., Ota M., Nagafuchi Y., Sumitomo S., Okamura T., Elkon K., Ishigaki K., Suzuki A., Kochi Y., Yamamoto K., Fujio K.

Annals of the Rheumatic Diseases 81 ( 6 ) 845 - 853 2022.06

ISSN 00034967

Objective Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease. While the long-term prognosis has greatly improved, better long-term survival is still necessary. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor. To explore immunological pathways in SLE more precisely, we performed transcriptomic, epigenomic and genomic analyses using 19 immune cell subsets from peripheral blood. Methods We sorted 19 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 patients with SLE and 92 healthy controls. Combined differentially expressed genes and expression quantitative trait loci analysis was conducted to find key driver genes in SLE pathogenesis. Results We found transcriptomic, epigenetic and genetic importance of oxidative phosphorylation (OXPHOS)/mitochondrial dysfunction in SLE memory B cells. Particularly, we identified an OXPHOS-regulating gene, PRDX6 (peroxiredoxin 6), as a key driver in SLE B cells. Prdx6-deficient B cells showed upregulated mitochondrial respiration as well as antibody production. We revealed OXPHOS signature was associated with type I IFN signalling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signalling among ISRGs presented correlation with OXPHOS and these two signatures showed associations with SLE organ damage as well as specific clinical phenotypes. Conclusion This work elucidated the potential prognostic marker for SLE. Since OXPHOS consists of the electron transport chain, a functional unit in mitochondria, these findings suggest the importance of mitochondrial dysfunction as a key immunological pathway involved in SLE.

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HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors

Ishigaki K., Lagattuta K.A., Luo Y., James E.A., Buckner J.H., Raychaudhuri S.

Nature Genetics (Springer Science and Business Media {LLC}) 54 ( 4 ) 393 - 402 2022.04

ISSN 10614036

Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA–CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by the HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (for example, citrullinated epitope-specific TCRs in patients with rheumatoid arthritis). Together, these results provide genetic evidence supporting the central hypothesis.

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Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate

Lagattuta K.A., Kang J.B., Nathan A., Pauken K.E., Jonsson A.H., Rao D.A., Sharpe A.H., Ishigaki K., Raychaudhuri S.

Nature Immunology 23 ( 3 ) 446 - 457 2022.03

ISSN 15292908

T cells acquire a regulatory phenotype when their T cell antigen receptors (TCRs) experience an intermediate- to high-affinity interaction with a self-peptide presented via the major histocompatibility complex (MHC). Using TCRβ sequences from flow-sorted human cells, we identified TCR features that promote regulatory T cell (T<inf>reg</inf>) fate. From these results, we developed a scoring system to quantify TCR-intrinsic regulatory potential (TiRP). When applied to the tumor microenvironment, TiRP scoring helped to explain why only some T cell clones maintained the conventional T cell (T<inf>conv</inf>) phenotype through expansion. To elucidate drivers of these predictive TCR features, we then examined the two elements of the T<inf>reg</inf> TCR ligand separately: the self-peptide and the human MHC class II molecule. These analyses revealed that hydrophobicity in the third complementarity-determining region (CDR3β) of the TCR promotes reactivity to self-peptides, while TCR variable gene (TRBV gene) usage shapes the TCR’s general propensity for human MHC class II-restricted activation.

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A FLOT1 host regulatory allele is associated with a recently expanded Mtb clade in patients with tuberculosis

Yang Luo and Chuan-Chin Huang and Qingyun Liu and Nicole Howard and Xinyi Li and Junhao Zhu and Tiffany Amariuta and Samira Asgari and Kazuyoshi Ishigaki and Roger Calderon and D. Branch Moody and Leonid Lecca and Sarah M Fortune and Megan B Murray and Soumya Raychaudhuri

(Cold Spring Harbor Laboratory) 2022.02

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Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci

2022.01

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Beyond GWAS: from simple associations to functional insights

Ishigaki K.

Seminars in Immunopathology (Springer Science and Business Media {LLC}) 44 ( 1 ) 3 - 14 2022.01

ISSN 18632297

Each human, when born, has slightly different DNA sequences, which make each of us unique. The variations in DNA sequences are called genetic variants. The primary aim of genome-wide association study (GWAS) is to detect associations between genetic variants and human phenotypes. Since GWAS focuses on germ-line variants, there is no reverse causation. Therefore, GWAS is one of the few tools that can assess the causality of human diseases. In the past 10 years, many large-scale GWAS have been conducted. Although the primary outputs of GWAS are just a series of statistics, its downstream analyses provided many insights beyond simple associations: the causal mechanisms for autoimmune diseases and shared etiology between diseases. Moreover, GWAS downstream analyses generated scores potentially helpful in predicting clinical outcomes of each patient. This review focuses on GWAS for autoimmune diseases and introduces significant achievements of its downstream analyses. We also provide future directions that potentially overcome current limitations. We restrict our discussion to common autoimmune diseases (e.g., rheumatoid arthritis) since rare Mendelian diseases possess distinct genetic etiologies and are not tested by GWAS.

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