DOCK2 is involved in the host genetics and biology of severe COVID-19
Authors: 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 ,   The Biobank Japan Project, Matsuda Koichi , Yamanashi Yuji , Furukawa Yoichi , Morisaki Takayuki , Murakami Yoshinori , Kamatani Yoichiro , Muto Kaori , Nagai Akiko , Obara Wataru , Yamaji Ken , Takahashi Kazuhisa , 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 , Okada Yukinori 
Published: August 2022

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 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.