Deciphering state-dependent immune features from multi-layer omics data at single-cell resolution
Ryuya Edahiro, Go Sato, Tatsuhiko Naito, Yuya Shirai, Ryunosuke Saiki, Kyuto Sonehara, Yoshihiko Tomofuji, Kenichi Yamamoto, Shinichi Namba, Noah Sasa, Genta Nagao, Qingbo S. Wang, Yugo Takahashi, Takanori Hasegawa, Toshihiro Kishikawa, Ken Suzuki, Yu‐Chen Liu, Daisuke Motooka, Ayako Takuwa, Hiromu Tanaka, Shuhei Azekawa, Japan COVID-19 Task Force, Qingbo S. Wang, Ryuya Edahiro, Yuya Shirai, Ho Lee, Takayoshi Hyugaji, Eigo Shimizu, Kotoe Katayama, Masahiro Kanai, Tatsuhiko Naito, Noah Sasa, Kazuhisa Takahashi, Norihiro Harada, Toshio Naito, Makoto Hiki, Yasushi Matsushita, Haruhi Takagi, Masako Ichikawa, Ai Nakamura, Sonoko Harada, Yuuki Sandhu, Hiroki Kabata, Katsunori Masaki, Hirofumi Kamata, Shinnosuke Ikemura, Shotaro Chubachi, Satoshi Okamori, Hideki Terai, Atsuho Morita, Takanori Asakura, Junichi Sasaki, Hiroshi Morisaki, Yoshifumi Uwamino, Kosaku Nanki, Sho Uchida, Shunsuke Uno, Tomoyasu Nishimura, Takashi Ishiguro, Taisuke Isono, Shun Shibata, Yuma Matsui, Chiaki Hosoda, Kenji Takano, Takashi Nishida, Yoichi Kobayashi, Yotaro Takaku, Noboru Takayanagi, Soichiro Ueda, Ai Tada, Masayoshi Miyawaki, Masaomi Yamamoto, Eriko Yoshida, Reina Hayashi, Tomoki Nagasaka, Sawako Arai, Yutaro Kaneko, Kana Sasaki, Etsuko Tagaya, Masatoshi Kawana, Ken Arimura, Kunihiko Takahashi, Tatsuhiko Anzai, Satoshi Ito, Akifumi Endo, Yuji Uchimura, Yasunari Miyazaki, Takayuki Honda, Tomoya Tateishi, Shuji Tohda, Naoya Ichimura, Kazunari Sonobe, Chihiro Tani Sassa, Jun Nakajima, Yasushi Nakano, Yukiko Nakajima, Ryusuke Anan, Ryosuke Arai, Yuko Kurihara, Yuko Harada
Abstract
Current molecular quantitative trait locus catalogs are mostly at bulk resolution and centered on Europeans. Here, we constructed an immune cell atlas with single-cell transcriptomics of >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics and gut metagenomics from 235 Japanese persons, including patients with coronavirus disease 2019 (COVID-19) and healthy individuals. We mapped germline genetic effects on gene expression within immune cell types and across cell states. We elucidated cell type- and context-specific human leukocyte antigen (HLA) and genome-wide associations with T and B cell receptor repertoires. Colocalization using dynamic genetic regulation provided better understanding of genome-wide association signals. Differential gene and protein expression analyses depicted cell type- and context-specific effects of polygenic risks. Various somatic mutations including mosaic chromosomal alterations, loss of Y chromosome and mitochondrial DNA (mtDNA) heteroplasmy were projected into single-cell resolution. We identified immune features specific to somatically mutated cells. Overall, immune cells are dynamically regulated in a cell state-dependent manner characterized with multiomic profiles. A single-cell multiomic immune cell atlas from 235 Japanese, including patients with COVID-19 and healthy individuals, linked with host genetics including germline and somatic mutation, plasma proteomics and metagenomics data reveals that immune cells are dynamically regulated in a cell state-dependent manner.