The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.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

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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

Interplay of irreversible reactions and deformation: a case of hydrofracturing in the rodingite\u2013serpentinite system

Abstract The interplay of irreversible reactions and deformation during regional metamorphism was analyzed in the reaction zones between rodingite and serpentinite. Rodingites are leucocratic rocks found commonly in serpentinites and are considered metasomatic products of Ca-rich fluid. Rodingites occur ubiquitously in serpentinite from the Nomo metamorphic rocks, western Kyushu, a Cretaceous accretionary complex of greenschist to epidote\u2013amphibolite facies condition. We used the singular value decomposition (SVD) method to analyze rodingitization reactions based on mineral compositions of a rodingite sample and a possible protolith (clinopyroxene gabbro). The resultant reaction implied that the rodingite was formed due to the addition of considerable amounts of CaO and H 2 O to the protolith, whereas other components such as SiO 2 , AF (Al 2 O 3 \u2009+\u2009Fe 2 O 3 ), and FM (FeO\u2009+\u2009MgO) were conserved. The Nomo rodingites are associated with reaction zones between serpentinite. A careful study on the compositional variations of diopside and chlorite in the rodingite, serpentinite, and the reaction zones between them showed a disequilibrium crystallization of diopside in the reaction zone. Diopside shows a serrated variation in composition across the reaction zone together with disequilibrium signature within grains (composite grain consisting of Fe-rich and Fe-poor parts). These features clearly indicate that diopside crystallized in a relatively short period compared to the metamorphism by irreversible reactions. Another conspicuous feature is that perovskite occurs in some reaction zones, whereas titanite is common in rodingites; this indicates that the reaction zone is poorer in SiO 2 . The tremolite veins are typically derived from the reaction zone into serpentinite; showing this is a good example of hydrofracturing associated with the formation of the reaction zone. All the reactions obtained by the SVD method that contribute to the formation of the reaction zones consumed CaO and evolved H 2 O, strongly suggesting that the hydrofracturing is caused by a rapid increment of fluid pressure during the progression of the reactions. The reactions consumed considerable amounts of SiO 2 in the reaction zone, which is consistent with the occurrence of perovskite, and the conservation of AF and FM components

チュウブ キュウシュウ ヒゴ タイ ナラビニ クロセ ガワ コウゾウ タイ ガ チョウ コウアツ ヘンセイ タイ デ アル カノウセイ ノ ケンショウ

九州中部肥後帯中の肥後変成岩類ならびに黒瀬川構造帯中の変成岩類の岩石学的研究を行い，これらが中国大陸超高圧変成帯（Kinlin-Dabie-Sulu UHP terrane）の断片であるという仮説の検討を行った．その結果，超高圧鉱物の発見には至らなかったものの，肥後変成岩類中の石灰珪質片麻岩中からザクロ石＋単斜輝石の鉱物組み合わせを見出し，その形成条件が約800 度，900MPa であることを明らかにした．この変成条件は従来高温低圧型とされてきた肥後変成岩類の変成条件よりも明らかに高圧であり，肥後変成岩類の変成条件の見直しが必要であることを示した．現在さらに高圧の条件を示す岩石を発見し，研究中であり，本研究は九州中部変成帯研究に新たな視座を与えるであろう．黒瀬川帯の変成岩については，蛇紋岩 中の構造岩塊として産する含ヒスイ輝石オンファス輝石曹長岩の形成条件を検討し，この岩石が350 度程度，500MPa-1.1GPa の温度圧力条件で形成されたことを示した．これにより九州中部黒瀬川構造帯にも低温高圧型変成岩が含まれることが明らかになった