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

Author

Namkoong, Ho, Edahiro, Ryuya, Takano, Tomomi, Nishihara, Hiroshi, Shirai, Yuya, Sonehara, Kyuto, Tanaka, Hiromu, Azekawa, Shuhei, Mikami, Yohei, Lee, Ho, Hasegawa, Takanori, Okudela, Koji, Okuzaki, Daisuke, Motooka, Daisuke, Kanai, Masahiro, Naito, Tatsuhiko, Yamamoto, Kenichi, Wang, Qingbo S., Saiki, Ryunosuke, Ishihara, Rino, Matsubara, Yuta, Hamamoto, Junko, Hayashi, Hiroyuki, Yoshimura, Yukihiro, Tachikawa, Natsuo, Yanagita, Emmy, Hyugaji, Takayoshi, Shimizu, Eigo, Katayama, Kotoe, Kato, Yasuhiro, Morita, Takayoshi, Takahashi, Kazuhisa, Harada, Norihiro, Naito, Toshio, Hiki, Makoto, Matsushita, Yasushi, Takagi, Haruhi, Aoki, Ryousuke, Nakamura, Ai, Harada, Sonoko, Sasano, Hitoshi, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Morita, Atsuho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Uchida, Sho, Uno, Shunsuke, Nishimura, Tomoyasu, Ishiguro, Takashi, Isono, Taisuke, Shibata, Shun, Matsui, Yuma, Hosoda, Chiaki, Takano, Kenji, Nishida, Takashi, Kobayashi, Yoichi, Takaku, Yotaro, Takayanagi, Noboru, Ueda, Soichiro, Tada, Ai, Miyawaki, Masayoshi, Yamamoto, Masaomi, Yoshida, Eriko, Hayashi, Reina, Nagasaka, Tomoki, Arai, Sawako, Kaneko, Yutaro, Sasaki, Kana, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Takahashi, Kunihiko, Anzai, Tatsuhiko, Ito, Satoshi, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro Tani, Nakajima, Jun, Nakano, Yasushi, Nakajima, Yukiko, Anan, Ryusuke, Arai, Ryosuke, Kurihara, Yuko, Harada, Yuko, Nishio, Kazumi, Ueda, Tetsuya, Azuma, Masanori, Saito, Ryuichi, Sado, Toshikatsu, Miyazaki, Yoshimune, Sato, Ryuichi, Haruta, Yuki, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Kimura, Tomoki, Sato, Tomonori, Takei, Reoto, Hagimoto, Satoshi, Noguchi, Yoichiro, Yamano, Yasuhiko, Sasano, Hajime, Ota, Sho, Nakamori, Yasushi, Yoshiya, Kazuhisa, Saito, Fukuki, Yoshihara, Tomoyuki, Wada, Daiki, Iwamura, Hiromu, Kanayama, Syuji, Maruyama, Shuhei, Yoshiyama, Takashi, Ohta, Ken, Kokuto, Hiroyuki, Ogata, Hideo, Tanaka, Yoshiaki, Arakawa, Kenichi, Shimoda, Masafumi, Osawa, Takeshi, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Kawada, Miki, Horinouchi, Hirohisa, Saito, Fumitake, Mitamura, Keiko, Hagihara, Masao, Ochi, Junichi, Uchida, Tomoyuki, Baba, Rie, Arai, Daisuke, Ogura, Takayuki, Takahashi, Hidenori, Hagiwara, Shigehiro, Nagao, Genta, Konishi, Shunichiro, Nakachi, Ichiro, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Sano, Hirohito, Matsumoto, Shuichiro, Kimura, Nozomu, Ono, Yoshinao, Baba, Hiroaki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Namba, Shinichi, Suzuki, Ken, Naito, Yoko, Liu, Yu-Chen, Takuwa, Ayako, Sugihara, Fuminori, Wing, James B., Sakakibara, Shuhei, Hizawa, Nobuyuki, Shiroyama, Takayuki, Miyawaki, Satoru, Kawamura, Yusuke, Nakayama, Akiyoshi, Matsuo, Hirotaka, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Yamaguchi, Yuta, Murakami, Teruaki, Kuge, Tomoki, Matsumoto, Kinnosuke, Yamamoto, Yuji, Yamamoto, Makoto, Yoneda, Midori, Kishikawa, Toshihiro, Yamada, Shuhei, Kawabata, Shuhei, Kijima, Noriyuki, Takagaki, Masatoshi, Sasa, Noah, Ueno, Yuya, Suzuki, Motoyuki, Takemoto, Norihiko, Eguchi, Hirotaka, Fukusumi, Takahito, Imai, Takao, Fukushima, Munehisa, Kishima, Haruhiko, Inohara, Hidenori, Tomono, Kazunori, Kato, Kazuto, Takahashi, Meiko, Matsuda, Fumihiko, Hirata, Haruhiko, Takeda, Yoshito, Koh, Hidefumi, Manabe, Tadashi, Funatsu, Yohei, Ito, Fumimaro, Fukui, Takahiro, Shinozuka, Keisuke, Kohashi, Sumiko, Miyazaki, Masatoshi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Takaoka, Hatsuyo, Watanabe, Kazuyoshi, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Sugimoto, Hideyasu, Kamiya, Akane, Kuwahara, Naota, Fujiwara, Akiko, Matsunaga, Tomohiro, Sato, Yoko, Okada, Takenori, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Nishi, Koichi, Nishitsuji, Masaru, Tani, Mayuko, Suzuki, Junya, Nakatsumi, Hiroki, Ogura, Takashi, Kitamura, Hideya, Hagiwara, Eri, Murohashi, Kota, Okabayashi, Hiroko, Mochimaru, Takao, Nukaga, Shigenari, Satomi, Ryosuke, Oyamada, Yoshitaka, Mori, Nobuaki, Baba, Tomoya, Fukui, Yasutaka, Odate, Mitsuru, Mashimo, Shuko, Makino, Yasushi, Yagi, Kazuma, Hashiguchi, Mizuha, Kagyo, Junko, Shiomi, Tetsuya, Fuke, Satoshi, Saito, Hiroshi, Tsuchida, Tomoya, Fujitani, Shigeki, Takita, Mumon, Morikawa, Daiki, Yoshida, Toru, Izumo, Takehiro, Inomata, Minoru, Kuse, Naoyuki, Awano, Nobuyasu, Tone, Mari, Ito, Akihiro, Nakamura, Yoshihiko, Hoshino, Kota, Maruyama, Junichi, Ishikura, Hiroyasu, Takata, Tohru, Odani, Toshio, Amishima, Masaru, Hattori, Takeshi, Shichinohe, Yasuo, Kagaya, Takashi, Kita, Toshiyuki, Ohta, Kazuhide, Sakagami, Satoru, Koshida, Kiyoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Kozu, Yutaka, Hiranuma, Hisato, Gon, Yasuhiro, Izumi, Namiki, Nagata, Kaoru, Ueda, Ken, Taki, Reiko, Hanada, Satoko, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Muranaka, Hiroyuki, Nakamura, Kazunori, Hashimoto, Naozumi, Wakahara, Keiko, Koji, Sakamoto, Omote, Norihito, Ando, Akira, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Kuraki, Takashige, Matsumoto, Takemasa, Yokote, Koutaro, Nakada, Taka-Aki, Abe, Ryuzo, Oshima, Taku, Shimada, Tadanaga, Harada, Masahiro, Takahashi, Takeshi, Ono, Hiroshi, Sakurai, Toshihiro, Shibusawa, Takayuki, Kimizuka, Yoshifumi, Kawana, Akihiko, Sano, Tomoya, Watanabe, Chie, Suematsu, Ryohei, Sageshima, Hisako, Yoshifuji, Ayumi, Ito, Kazuto, Takahashi, Saeko, Ishioka, Kota, Nakamura, Morio, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Ueda, Suguru, Nishikawa, Masanori, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Shinozuka, Jun, Sueyoshi, Atsushi, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Shimo, Masatoshi, Tokunaga, Yoshihisa, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Ogawa, Aki, Inoue, Takuya, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Kan-o, Keiko, Matsumoto, Koichiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Inoue, Yoshiaki, Chiba, Shigeru, Yamagata, Kunihiro, Hiramatsu, Yuji, Kai, Hirayasu, Asano, Koichiro, Oguma, Tsuyoshi, Ito, Yoko, Hashimoto, Satoru, Yamasaki, Masaki, Kasamatsu, Yu, Komase, Yuko, Hida, Naoya, Tsuburai, Takahiro, Oyama, Baku, Takada, Minoru, Kanda, Hidenori, Kitagawa, Yuichiro, Fukuta, Tetsuya, Miyake, Takahito, Yoshida, Shozo, Ogura, Shinji, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Takoi, Hiroyuki, Kikuchi, Ryota, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Wada, Sae, Fujimoto, Nobukazu, Nishiyama, Kei, Terashima, Mariko, Beppu, Satoru, Yoshida, Kosuke, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Umeda, Akira, Miyagawa, Kazuya, Shimada, Hisato, Endo, Mayu, Ohira, Yoshiyuki, Watanabe, Masafumi, Inoue, Sumito, Igarashi, Akira, Sato, Masamichi, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Kimura, Tomoyuki, Shibata, Yoko, Tanino, Yoshinori, Nikaido, Takefumi, Minemura, Hiroyuki, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Takahashi, Hiroshi, Fujii, Kazuhiko, Kishi, Hiroto, Kanai, Masayuki, Imamura, Tomonori, Yamashita, Tatsuya, Yatomi, Masakiyo, Maeno, Toshitaka, Hayashi, Shinichi, Takahashi, Mai, Kuramochi, Mizuki, Kamimaki, Isamu, Tominaga, Yoshiteru, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Tanaka, Toru, Kashiwada, Takeru, Fujita, Kazue, Saito, Yoshinobu, Seike, Masahiro, Watanabe, Hiroko, Matsuse, Hiroto, Kodaka, Norio, Nakano, Chihiro, Oshio, Takeshi, Hirouchi, Takatomo, Makino, Shohei, Egi, Moritoki, Matsuda, Koichi, Yamanashi, Yuji, Furukawa, Yoichi, Morisaki, Takayuki, Murakami, Yoshinori, Kamatani, Yoichiro, Muto, Kaori, Nagai, Akiko, Obara, Wataru, Yamaji, Ken, Asai, Satoshi, Takahashi, Yasuo, Suzuki, Takao, Sinozaki, Nobuaki, Yamaguchi, Hiroki, Minami, Shiro, Murayama, Shigeo, Yoshimori, Kozo, Nagayama, Satoshi, Obata, Daisuke, Higashiyama, Masahiko, Masumoto, Akihide, Koretsune, Yukihiro, Omae, Yosuke, Nannya, Yasuhito, Ueno, Takafumi, Katayama, Kazuhiko, Ai, Masumi, Fukui, Yoshinori, Kumanogoh, Atsushi, Sato, Toshiro, Hasegawa, Naoki, Tokunaga, Katsushi, Ishii, Makoto, Koike, Ryuji, Kitagawa, Yuko, Kimura, Akinori, Imoto, Seiya, Miyano, Satoru, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, and Okada, Yukinori

Subjects
Genome-wide association studies, Japan, Genetics research, Weight Loss, Immunogenetics, Animals, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, RNA-Seq, Lung, Alleles, Multidisciplinary, Host Microbial Interactions, Mesocricetus, SARS-CoV-2, Macrophages, GTPase-Activating Proteins, COVID-19, Pneumonia, Middle Aged, Viral Load, Disease Models, Animal, Viral infection, Interferon Type I, Pyrazoles, Genome-Wide Association Study
Abstract

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., 「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.

Published
2021

2. DOCK2is involved in the host genetics and biology of severe COVID-19

Author

Namkoong, Ho, Edahiro, Ryuya, Takano, Tomomi, Nishihara, Hiroshi, Shirai, Yuya, Sonehara, Kyuto, Tanaka, Hiromu, Azekawa, Shuhei, Mikami, Yohei, Lee, Ho, Hasegawa, Takanori, Okudela, Koji, Okuzaki, Daisuke, Motooka, Daisuke, Kanai, Masahiro, Naito, Tatsuhiko, Yamamoto, Kenichi, Wang, Qingbo S., Saiki, Ryunosuke, Ishihara, Rino, Matsubara, Yuta, Hamamoto, Junko, Hayashi, Hiroyuki, Yoshimura, Yukihiro, Tachikawa, Natsuo, Yanagita, Emmy, Hyugaji, Takayoshi, Shimizu, Eigo, Katayama, Kotoe, Kato, Yasuhiro, Morita, Takayoshi, Takahashi, Kazuhisa, Harada, Norihiro, Naito, Toshio, Hiki, Makoto, Matsushita, Yasushi, Takagi, Haruhi, Aoki, Ryousuke, Nakamura, Ai, Harada, Sonoko, Sasano, Hitoshi, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Morita, Atsuho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Uchida, Sho, Uno, Shunsuke, Nishimura, Tomoyasu, Ishiguro, Takashi, Isono, Taisuke, Shibata, Shun, Matsui, Yuma, Hosoda, Chiaki, Takano, Kenji, Nishida, Takashi, Kobayashi, Yoichi, Takaku, Yotaro, Takayanagi, Noboru, Ueda, Soichiro, Tada, Ai, Miyawaki, Masayoshi, Yamamoto, Masaomi, Yoshida, Eriko, Hayashi, Reina, Nagasaka, Tomoki, Arai, Sawako, Kaneko, Yutaro, Sasaki, Kana, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Takahashi, Kunihiko, Anzai, Tatsuhiko, Ito, Satoshi, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro Tani, Nakajima, Jun, Nakano, Yasushi, Nakajima, Yukiko, Anan, Ryusuke, Arai, Ryosuke, Kurihara, Yuko, Harada, Yuko, Nishio, Kazumi, Ueda, Tetsuya, Azuma, Masanori, Saito, Ryuichi, Sado, Toshikatsu, Miyazaki, Yoshimune, Sato, Ryuichi, Haruta, Yuki, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Kimura, Tomoki, Sato, Tomonori, Takei, Reoto, Hagimoto, Satoshi, Noguchi, Yoichiro, Yamano, Yasuhiko, Sasano, Hajime, Ota, Sho, Nakamori, Yasushi, Yoshiya, Kazuhisa, Saito, Fukuki, Yoshihara, Tomoyuki, Wada, Daiki, Iwamura, Hiromu, Kanayama, Syuji, Maruyama, Shuhei, Yoshiyama, Takashi, Ohta, Ken, Kokuto, Hiroyuki, Ogata, Hideo, Tanaka, Yoshiaki, Arakawa, Kenichi, Shimoda, Masafumi, Osawa, Takeshi, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Kawada, Miki, Horinouchi, Hirohisa, Saito, Fumitake, Mitamura, Keiko, Hagihara, Masao, Ochi, Junichi, Uchida, Tomoyuki, Baba, Rie, Arai, Daisuke, Ogura, Takayuki, Takahashi, Hidenori, Hagiwara, Shigehiro, Nagao, Genta, Konishi, Shunichiro, Nakachi, Ichiro, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Sano, Hirohito, Matsumoto, Shuichiro, Kimura, Nozomu, Ono, Yoshinao, Baba, Hiroaki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Namba, Shinichi, Suzuki, Ken, Naito, Yoko, Liu, Yu-Chen, Takuwa, Ayako, Sugihara, Fuminori, Wing, James B., Sakakibara, Shuhei, Hizawa, Nobuyuki, Shiroyama, Takayuki, Miyawaki, Satoru, Kawamura, Yusuke, Nakayama, Akiyoshi, Matsuo, Hirotaka, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Yamaguchi, Yuta, Murakami, Teruaki, Kuge, Tomoki, Matsumoto, Kinnosuke, Yamamoto, Yuji, Yamamoto, Makoto, Yoneda, Midori, Kishikawa, Toshihiro, Yamada, Shuhei, Kawabata, Shuhei, Kijima, Noriyuki, Takagaki, Masatoshi, Sasa, Noah, Ueno, Yuya, Suzuki, Motoyuki, Takemoto, Norihiko, Eguchi, Hirotaka, Fukusumi, Takahito, Imai, Takao, Fukushima, Munehisa, Kishima, Haruhiko, Inohara, Hidenori, Tomono, Kazunori, Kato, Kazuto, Takahashi, Meiko, Matsuda, Fumihiko, Hirata, Haruhiko, Takeda, Yoshito, Koh, Hidefumi, Manabe, Tadashi, Funatsu, Yohei, Ito, Fumimaro, Fukui, Takahiro, Shinozuka, Keisuke, Kohashi, Sumiko, Miyazaki, Masatoshi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Takaoka, Hatsuyo, Watanabe, Kazuyoshi, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Sugimoto, Hideyasu, Kamiya, Akane, Kuwahara, Naota, Fujiwara, Akiko, Matsunaga, Tomohiro, Sato, Yoko, Okada, Takenori, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Nishi, Koichi, Nishitsuji, Masaru, Tani, Mayuko, Suzuki, Junya, Nakatsumi, Hiroki, Ogura, Takashi, Kitamura, Hideya, Hagiwara, Eri, Murohashi, Kota, Okabayashi, Hiroko, Mochimaru, Takao, Nukaga, Shigenari, Satomi, Ryosuke, Oyamada, Yoshitaka, Mori, Nobuaki, Baba, Tomoya, Fukui, Yasutaka, Odate, Mitsuru, Mashimo, Shuko, Makino, Yasushi, Yagi, Kazuma, Hashiguchi, Mizuha, Kagyo, Junko, Shiomi, Tetsuya, Fuke, Satoshi, Saito, Hiroshi, Tsuchida, Tomoya, Fujitani, Shigeki, Takita, Mumon, Morikawa, Daiki, Yoshida, Toru, Izumo, Takehiro, Inomata, Minoru, Kuse, Naoyuki, Awano, Nobuyasu, Tone, Mari, Ito, Akihiro, Nakamura, Yoshihiko, Hoshino, Kota, Maruyama, Junichi, Ishikura, Hiroyasu, Takata, Tohru, Odani, Toshio, Amishima, Masaru, Hattori, Takeshi, Shichinohe, Yasuo, Kagaya, Takashi, Kita, Toshiyuki, Ohta, Kazuhide, Sakagami, Satoru, Koshida, Kiyoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Kozu, Yutaka, Hiranuma, Hisato, Gon, Yasuhiro, Izumi, Namiki, Nagata, Kaoru, Ueda, Ken, Taki, Reiko, Hanada, Satoko, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Muranaka, Hiroyuki, Nakamura, Kazunori, Hashimoto, Naozumi, Wakahara, Keiko, Sakamoto, Koji, Omote, Norihito, Ando, Akira, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Kuraki, Takashige, Matsumoto, Takemasa, Yokote, Koutaro, Nakada, Taka-Aki, Abe, Ryuzo, Oshima, Taku, Shimada, Tadanaga, Harada, Masahiro, Takahashi, Takeshi, Ono, Hiroshi, Sakurai, Toshihiro, Shibusawa, Takayuki, Kimizuka, Yoshifumi, Kawana, Akihiko, Sano, Tomoya, Watanabe, Chie, Suematsu, Ryohei, Sageshima, Hisako, Yoshifuji, Ayumi, Ito, Kazuto, Takahashi, Saeko, Ishioka, Kota, Nakamura, Morio, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Ueda, Suguru, Nishikawa, Masanori, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Shinozuka, Jun, Sueyoshi, Atsushi, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Shimo, Masatoshi, Tokunaga, Yoshihisa, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Ogawa, Aki, Inoue, Takuya, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Kan-o, Keiko, Matsumoto, Koichiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Inoue, Yoshiaki, Chiba, Shigeru, Yamagata, Kunihiro, Hiramatsu, Yuji, Kai, Hirayasu, Asano, Koichiro, Oguma, Tsuyoshi, Ito, Yoko, Hashimoto, Satoru, Yamasaki, Masaki, Kasamatsu, Yu, Komase, Yuko, Hida, Naoya, Tsuburai, Takahiro, Oyama, Baku, Takada, Minoru, Kanda, Hidenori, Kitagawa, Yuichiro, Fukuta, Tetsuya, Miyake, Takahito, Yoshida, Shozo, Ogura, Shinji, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Takoi, Hiroyuki, Kikuchi, Ryota, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Wada, Sae, Fujimoto, Nobukazu, Nishiyama, Kei, Terashima, Mariko, Beppu, Satoru, Yoshida, Kosuke, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Umeda, Akira, Miyagawa, Kazuya, Shimada, Hisato, Endo, Mayu, Ohira, Yoshiyuki, Watanabe, Masafumi, Inoue, Sumito, Igarashi, Akira, Sato, Masamichi, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Kimura, Tomoyuki, Shibata, Yoko, Tanino, Yoshinori, Nikaido, Takefumi, Minemura, Hiroyuki, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Takahashi, Hiroshi, Fujii, Kazuhiko, Kishi, Hiroto, Kanai, Masayuki, Imamura, Tomonori, Yamashita, Tatsuya, Yatomi, Masakiyo, Maeno, Toshitaka, Hayashi, Shinichi, Takahashi, Mai, Kuramochi, Mizuki, Kamimaki, Isamu, Tominaga, Yoshiteru, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Tanaka, Toru, Kashiwada, Takeru, Fujita, Kazue, Saito, Yoshinobu, Seike, Masahiro, Watanabe, Hiroko, Matsuse, Hiroto, Kodaka, Norio, Nakano, Chihiro, Oshio, Takeshi, Hirouchi, Takatomo, Makino, Shohei, Egi, Moritoki, Omae, Yosuke, Nannya, Yasuhito, Ueno, Takafumi, Katayama, Kazuhiko, Ai, Masumi, Fukui, Yoshinori, Kumanogoh, Atsushi, Sato, Toshiro, Hasegawa, Naoki, Tokunaga, Katsushi, Ishii, Makoto, Koike, Ryuji, Kitagawa, Yuko, Kimura, Akinori, Imoto, Seiya, Miyano, Satoru, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, and Okada, Yukinori

Abstract

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. 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 DOCK2associated with the risk allele in these younger patients. DOCK2expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n= 61 individuals) identified cell-type-specific downregulation of DOCK2and a COVID-19-specific decreasing effect of the risk allele on DOCK2expression 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.

Published
2022
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3. DOCK2 is involved in the host genetics and biology of severe COVID-19.

Author

Namkoong H, Edahiro R, Takano T, Nishihara H, Shirai Y, Sonehara K, Tanaka H, Azekawa S, Mikami Y, Lee H, Hasegawa T, Okudela K, Okuzaki D, Motooka D, Kanai M, Naito T, Yamamoto K, Wang QS, Saiki R, Ishihara R, Matsubara Y, Hamamoto J, Hayashi H, Yoshimura Y, Tachikawa N, Yanagita E, Hyugaji T, Shimizu E, Katayama K, Kato Y, Morita T, Takahashi K, Harada N, Naito T, Hiki M, Matsushita Y, Takagi H, Aoki R, Nakamura A, Harada S, Sasano H, Kabata H, Masaki K, Kamata H, Ikemura S, Chubachi S, Okamori S, Terai H, Morita A, Asakura T, Sasaki J, Morisaki H, Uwamino Y, Nanki K, Uchida S, Uno S, Nishimura T, Ishiguro T, Isono T, Shibata S, Matsui Y, Hosoda C, Takano K, Nishida T, Kobayashi Y, Takaku Y, Takayanagi N, Ueda S, Tada A, Miyawaki M, Yamamoto M, Yoshida E, Hayashi R, Nagasaka T, Arai S, Kaneko Y, Sasaki K, Tagaya E, Kawana M, Arimura K, Takahashi K, Anzai T, Ito S, Endo A, Uchimura Y, Miyazaki Y, Honda T, Tateishi T, Tohda S, Ichimura N, Sonobe K, Sassa CT, Nakajima J, Nakano Y, Nakajima Y, Anan R, Arai R, Kurihara Y, Harada Y, Nishio K, Ueda T, Azuma M, Saito R, Sado T, Miyazaki Y, Sato R, Haruta Y, Nagasaki T, Yasui Y, Hasegawa Y, Mutoh Y, Kimura T, Sato T, Takei R, Hagimoto S, Noguchi Y, Yamano Y, Sasano H, Ota S, Nakamori Y, Yoshiya K, Saito F, Yoshihara T, Wada D, Iwamura H, Kanayama S, Maruyama S, Yoshiyama T, Ohta K, Kokuto H, Ogata H, Tanaka Y, Arakawa K, Shimoda M, Osawa T, Tateno H, Hase I, Yoshida S, Suzuki S, Kawada M, Horinouchi H, Saito F, Mitamura K, Hagihara M, Ochi J, Uchida T, Baba R, Arai D, Ogura T, Takahashi H, Hagiwara S, Nagao G, Konishi S, Nakachi I, Murakami K, Yamada M, Sugiura H, Sano H, Matsumoto S, Kimura N, Ono Y, Baba H, Suzuki Y, Nakayama S, Masuzawa K, Namba S, Suzuki K, Naito Y, Liu YC, Takuwa A, Sugihara F, Wing JB, Sakakibara S, Hizawa N, Shiroyama T, Miyawaki S, Kawamura Y, Nakayama A, Matsuo H, Maeda Y, Nii T, Noda Y, Niitsu T, Adachi Y, Enomoto T, Amiya S, Hara R, Yamaguchi Y, Murakami T, Kuge T, Matsumoto K, Yamamoto Y, Yamamoto M, Yoneda M, Kishikawa T, Yamada S, Kawabata S, Kijima N, Takagaki M, Sasa N, Ueno Y, Suzuki M, Takemoto N, Eguchi H, Fukusumi T, Imai T, Fukushima M, Kishima H, Inohara H, Tomono K, Kato K, Takahashi M, Matsuda F, Hirata H, Takeda Y, Koh H, Manabe T, Funatsu Y, Ito F, Fukui T, Shinozuka K, Kohashi S, Miyazaki M, Shoko T, Kojima M, Adachi T, Ishikawa M, Takahashi K, Inoue T, Hirano T, Kobayashi K, Takaoka H, Watanabe K, Miyazawa N, Kimura Y, Sado R, Sugimoto H, Kamiya A, Kuwahara N, Fujiwara A, Matsunaga T, Sato Y, Okada T, Hirai Y, Kawashima H, Narita A, Niwa K, Sekikawa Y, Nishi K, Nishitsuji M, Tani M, Suzuki J, Nakatsumi H, Ogura T, Kitamura H, Hagiwara E, Murohashi K, Okabayashi H, Mochimaru T, Nukaga S, Satomi R, Oyamada Y, Mori N, Baba T, Fukui Y, Odate M, Mashimo S, Makino Y, Yagi K, Hashiguchi M, Kagyo J, Shiomi T, Fuke S, Saito H, Tsuchida T, Fujitani S, Takita M, Morikawa D, Yoshida T, Izumo T, Inomata M, Kuse N, Awano N, Tone M, Ito A, Nakamura Y, Hoshino K, Maruyama J, Ishikura H, Takata T, Odani T, Amishima M, Hattori T, Shichinohe Y, Kagaya T, Kita T, Ohta K, Sakagami S, Koshida K, Hayashi K, Shimizu T, Kozu Y, Hiranuma H, Gon Y, Izumi N, Nagata K, Ueda K, Taki R, Hanada S, Kawamura K, Ichikado K, Nishiyama K, Muranaka H, Nakamura K, Hashimoto N, Wakahara K, Sakamoto K, Omote N, Ando A, Kodama N, Kaneyama Y, Maeda S, Kuraki T, Matsumoto T, Yokote K, Nakada TA, Abe R, Oshima T, Shimada T, Harada M, Takahashi T, Ono H, Sakurai T, Shibusawa T, Kimizuka Y, Kawana A, Sano T, Watanabe C, Suematsu R, Sageshima H, Yoshifuji A, Ito K, Takahashi S, Ishioka K, Nakamura M, Masuda M, Wakabayashi A, Watanabe H, Ueda S, Nishikawa M, Chihara Y, Takeuchi M, Onoi K, Shinozuka J, Sueyoshi A, Nagasaki Y, Okamoto M, Ishihara S, Shimo M, Tokunaga Y, Kusaka Y, Ohba T, Isogai S, Ogawa A, Inoue T, Fukuyama S, Eriguchi Y, Yonekawa A, Kan-O K, Matsumoto K, Kanaoka K, Ihara S, Komuta K, Inoue Y, Chiba S, Yamagata K, Hiramatsu Y, Kai H, Asano K, Oguma T, Ito Y, Hashimoto S, Yamasaki M, Kasamatsu Y, Komase Y, Hida N, Tsuburai T, Oyama B, Takada M, Kanda H, Kitagawa Y, Fukuta T, Miyake T, Yoshida S, Ogura S, Abe S, Kono Y, Togashi Y, Takoi H, Kikuchi R, Ogawa S, Ogata T, Ishihara S, Kanehiro A, Ozaki S, Fuchimoto Y, Wada S, Fujimoto N, Nishiyama K, Terashima M, Beppu S, Yoshida K, Narumoto O, Nagai H, Ooshima N, Motegi M, Umeda A, Miyagawa K, Shimada H, Endo M, Ohira Y, Watanabe M, Inoue S, Igarashi A, Sato M, Sagara H, Tanaka A, Ohta S, Kimura T, Shibata Y, Tanino Y, Nikaido T, Minemura H, Sato Y, Yamada Y, Hashino T, Shinoki M, Iwagoe H, Takahashi H, Fujii K, Kishi H, Kanai M, Imamura T, Yamashita T, Yatomi M, Maeno T, Hayashi S, Takahashi M, Kuramochi M, Kamimaki I, Tominaga Y, Ishii T, Utsugi M, Ono A, Tanaka T, Kashiwada T, Fujita K, Saito Y, Seike M, Watanabe H, Matsuse H, Kodaka N, Nakano C, Oshio T, Hirouchi T, Makino S, Egi M, Omae Y, Nannya Y, Ueno T, Katayama K, Ai M, Fukui Y, Kumanogoh A, Sato T, Hasegawa N, Tokunaga K, Ishii M, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, and Okada Y

Subjects
Alleles, Animals, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Interferon Type I genetics, Interferon Type I immunology, Japan, Lung pathology, Macrophages, Mesocricetus, Middle Aged, Pneumonia complications, Pyrazoles pharmacology, RNA-Seq, Viral Load, Weight Loss, COVID-19 complications, COVID-19 genetics, COVID-19 immunology, COVID-19 physiopathology, GTPase-Activating Proteins antagonists & inhibitors, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors antagonists & inhibitors, Guanine Nucleotide Exchange Factors genetics, Guanine Nucleotide Exchange Factors metabolism, Host Microbial Interactions genetics, Host Microbial Interactions immunology, SARS-CoV-2 pathogenicity
Abstract

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . 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., (© 2022. The Author(s).)

Published
2022
Full Text
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