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

Analyses of the Wind Damage Caused by Typhoon 15 in 1981 at Tokyo University Forest in Hokkaido

東京大学北海道演習林において，1981年夏の台風第15号により大規模な風害が発生した。そこで筆者らは，数量化による多変量解析の手法を用いて，被害率と地形および林況要因との関係を検討した。地形要因には，標高，露出度，斜面方位，斜面上の相対位置，斜面形状，傾斜角，土壌深をとり上げ，地形図および土壌図から読みとった。林況要因には，森林率，林冠疎密度，高木層のみの林冠疎密度，針葉樹混交率をとり上げ，空中写真から読みとった。多変量解析に先立って，被害率と各要因とを個別に比較した結果，露出度と斜面方位が被害発生に大きく関与することがわかった。数量化II類による判別分析では，無被害と小，中，激害の正判別率がいずれも70パーセント以上となり，かなりよく判別された。数量化I類による重回帰分析では，重相関係数は0.60であった。これらの多変量解析の結果から以下のことがわかった。i）周囲の3/4以上が露出していてかつ，斜面方位が暴風の主風方向を中心に左右約70°の範囲にある林分が，とくに大きな被害を受けた。ii）傾斜がゆるやかな林分および針葉樹混交率が高い林分も，概して被害を受けやすい傾向にあった。また，重回帰分析の予測値を用いて，調査地内の風害発生予測図を描くと，一部の地域を除いて実測値の分布図とよく一致した。The forests in Tokyo University Forest in Hokkaido were severely damaged by typhoon 15 in 1981. We tried analyses of the relation between wind damage and some topographical and certain stand condition factors by consulting topographical map, soil map and air photographs. Seven items for topographical factors―altitude, exposure, facing of the slope, relative position on the slope, land type on the slope (relief), inclination, soil depth―and 4 items for stand condition factors―forest area percentage, canopy density of trees higher than 4m, canopy density of trees higher than 14m and mixture percentage of conifer trees―were selected for quantification analyses. On the quantification analysis Hayashi-2, correct discrimination percentage between no damaged areas and damaged areas was more than 70 per cent. On the quantification analysis of Hayashi-1, multiple correlation coefficient was 0.60. Among the 11 items, exposure and facing of the slope were significantly related to the occurrence of wind damage. The following stands were severely damaged: those which face to the main direction of the stormy wind in the range of approximately 70 degree from the center. Generally, it is recognized that stands which are on gentle slopes or have high mixture percentage of conifer trees were easily damaged. As the result of drawing a predictive map of wind damage with the predictive scores of Hayashi-1, the map is generally fitted to the distribution of wind damage percentage of actual scores with some exceptions

Courses of Height Growth of Cryptomeria japonica Trees Planted on a Slope : Comparison among the near ridge, the mid-slope and the near bottom in the Tokyo University Forest in Chiba

東京大学千葉演習林において，スギ造林木の樹高生長経過と土壌の理化学性およびスギ針葉の養分濃度との関係を，斜面上部，中部，下部間で比較検討した。老齢林の樹高は，斜面上部から下部にむかうにしたがって高くなる傾向がみられたが，若齢林や幼齢造林地では，上部と下部との樹高差が著しい調査地と大差ない調査地とがみられた。樹幹解析によってえた老齢林2調査地の樹高生長経過は，中，下部では，両調査地ともそれぞれ対応する地位の樹高生長曲線と似ていた。一方，上部では，20～30年生頃までは樹高生長曲線とにた生長経過であるが，その後生長が頭打ちとなる調査地と初期生長はよくないが中～後期にかけてもあまり頭打ちにならない調査地とにわかれた。中～後期にかけて生長が頭打ちであった調査地の土層は薄く，あまり頭打ちのみられなかった調査地の土層は比較的厚かった。それぞれの調査地の初期生長経過のちがいは，それぞれの老齢林を皆伐した後に植栽されたスギ苗木の生長でもみられた。土壌の化学性は，中，下部では，調査地による差が小さかった。上部では，pH値等に違いがみられ，初期生長の良い調査地の土壌は，pH値が6以上と中性にちかく，生長の劣る調査地は，相対的に酸性度の強い土壌であった。土壌の化学性は，位置的に近く，母材の同じ調査地で似ていたことから，母材の違いが影響していると考えられる。幼齢造林地での葉分析の結果，斜面上部，中部，下部で，それぞれ樹高生長のよい調査区ほど，針葉の窒素濃度が高い傾向がみられた。窒素濃度が同程度の場合，中，下部に比べて，上部で生長が劣る傾向がみられた。調査地間での土壌の理化学性の差が小さい斜面中，下部では，樹高生長経過の調査地間での差が小さく，一方，上部では，調査地間で土壌の化学性や土層の厚さ等の差が大きく，それに対応して生育初期や中～後期の樹高生長経過の調査地間の差が大きかった。Differences in course of height growth of Cryptomeria japonica trees planted on a slope were compared among near ridge, mid-slope and near bottom. The study was made in 14 study areas in the Tokyo University Forest in Chiba and causes of the difference were discussed in relation to properties of soil and nutrients contents of needle. In study areas of older stands, the height of Cryptomeria tree increased from ridge to bottom along the slope, while of younger stands and younger plantations before canopy closing, this difference was various, apparent in some cases and not apparent in other cases. On mid-slope and near bottom in the two study areas of older stands, the courses of height growth observed by stem analysis paralleled with the curves in each corresponding site class of the yield table. Near ridge, the height growth followed the yield table until 20-30-yr-old and depressed thereafter in the one area where soil layer was thinner, and the growth was not excellent in early stage but the depression with age was not obvious in the other area where soil layer was thicker. The similar difference in height growth in early stage was seen in seedlings planted on the study areas after clear-cutting of older stands. Differences in chemical properties of soil among the study areas were found near ridge, but was not apparent on mid-slope and near bottom. The height growth was affected by pH of soil, the values higher than 6 resulted in excellent growth and lower values in poor one. The chemical properties of soil depended on bed rock. In each part along the slope, the height growth increased with nitrogen content of needle. In comparison of the same level of nitrogen content, the height growths on mid-slope and near bottom were higher than near ridge. The differences in height growth between on mid-slope and near bottom were smaller reflecting smaller differences in physical and chemical properties of soil among the study areas. But near ridge the course of height growth was various throughout the earlier, middle and later stages resulting from different soil properties among the study areas