A Schmidt, T. Madhusankha Alawathurage, Friederike S. David, Yosuke Ogawa, Leonard Frach, Sylvia Richter, M. Schaefer, Carina M. Mathey, Sabrina K. Henne, Japan COVID-19 Task Force, Genta Nagao, Hiromu Tanaka, Shuhei Azekawa, Ko Lee, Naoki Fukunaga, Junko Hamamoto, HIROKI KABATA, Katsunori Masaki, Hirofumi Kamata, Shinnosuke Ikemura, Shotaro Chubachi, Satoshi Okamori, Hideki Terai, A. Morita, Takanori Asakura, Makoto Ishii, Koichi Fukunaga, Y. Uwamino, Sho Uchida, Shunsuke Uno, Tomoyasu Nishimura, Naoki Hasegawa, Emmy Yanagita, Hiroshi Nishihara, Junichi Sasaki, Hiroshi Morisaki, Toshiro Sato, Yuko Kitagawa, Yuta Matsubara, Yohei Mikami, Kosaku Nanki, Takanori Kanai, Ryuya Edahiro, Yuya Shirai, Kyuto Sonehara, Daisuke Okuzaki, Daisuke Motooka, Masahiro Kanai, Tatsuhiko Naito, Kenichi Yamamoto, Qingbo Wang, Yasuhiro Kato, Takayoshi Morita, Shinichi Namba, Ken Suzuki, Yoko Naito, Yu-Chen Liu, Ayako Takuwa, Fuminori Sugihara, James B. Wing, Shuhei Sakakibara, Nobuyuki Hizawa, Takayuki Shiroyama, Satoru Miyawaki, Y. Kawamura, Akiyoshi Nakayama, Hirotaka Matsuo, Yuichi Maeda, Takuro Nii, Yoshimi Noda, Takayuki Niitsu, Yuichi Adachi, Takatoshi Enomoto, Saori Amiya, Reina Hara, Yuta Yamaguchi, Teruaki Murakami, Tomoki Kuge, Kinnosuke Matsumoto, Yuji Yamamoto, Makoto Yamamoto, Midori Yoneda, Toshihiro Kishikawa, Shuhei Yamada, Shuhei KAWABATA, Noriyuki Kijima, Masatoshi Takagaki, Noah Sasa, Yuya Ueno, 基之 鈴木, Norihiko Takemoto, Hirotaka Eguchi, Takahito Fukusumi, Takao Imai, Munehisa Fukushima, Haruhiko Kishima, Hidenori Inohara, Kazunori TOMONO, Kazuto Kato, Meiko Takahashi
Abstract Epstein–Barr virus (EBV) infects approximately 90–95% of the global population 1,2 and persists in B cells as a lifelong infection 3 . Previous EBV infection is associated with autoimmune and neoplastic disease 4 . Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread + ) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake and current smoking. Genome-wide analyses of EBVread + identified strong associations at the major histocompatibility complex (MHC), including 54 independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases 4 revealed a higher polygenic burden of EBVread + for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread + with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.