Identification and replication of sex-dimorphic protein quantitative trait loci across multiple ancestries and their associations with diseases
Males and females exhibit differences in proteome profiles associated with disease risk. However, sex-dimorphic protein quantitative trait loci (SD-pQTL) and their effects on sex differences in health disorders have not been thoroughly investigated. We conducted a sex-stratified, genome-wide association study on 2,922 proteins using data from 30,272 individuals of Caucasian ancestry from the UK Biobank and compared the estimated effects on protein levels of these variants in the men and women to identify SD-pQTLs. The identified SD-pQTLs were replicated using data from two Japanese cohorts (comprising 2,886 and 1,394 individuals, respectively), as well as from 1,990 Finnish, 630 South Asian, and 662 Black ancestry individuals. Sex-dimorphic pleiotropy and the causal relationship between protein levels and health disorders were assessed using the identified SD-pQTLs. We identified 113 SD-pQTLs associated with 65 proteins. Of the 113 SD-pQTLs, 52 were significant in both sexes, five were not significant in either sex, and 42 and 14 were significant only in males and females, respectively. Variant rs2270416 was significantly associated with the CDH15 protein in both sexes but showed opposite effect direction in men and women. Of the 113 SD-pQTLs identified, a total of 41 were replicated in a meta-analysis encompassing Japanese, South Asian, and Black ancestry individuals. SD-pQTLs for proteins APOE (rs157581) and SNAP25 (rs4420638) exhibited sex-dimorphic associations with dementia, indicating sex dimorphic pleiotropy in both proteins and health disorders. From sex-stratified Mendelian randomization using the SD-pQTLs, proteins NCAM1 and PZP showed significant causal relationship with dementia in males and females, respectively. The present study provides evidence of sex-dimorphic genetic architecture in protein-level regulation, elucidating the proteo-genetic architecture for sex differences in human variation.
Authors
- Hiroyuki Takoi (ORCID: https://orcid.org/0000-0002-6005-9253)
- Jun Shinozuka
- Koji Sakamoto (ORCID: https://orcid.org/0000-0002-1794-576X)
- Eriko Yoshida
- Kinnosuke Matsumoto (ORCID: https://orcid.org/0000-0002-4930-6997)
- Tohru Takata (ORCID: https://orcid.org/0000-0002-2593-2993)
- Mayu Endo
- Yotaro Takaku (ORCID: https://orcid.org/0000-0002-6431-192X)
- Daisuke Motooka (ORCID: https://orcid.org/0000-0002-4616-9608)
- Masayoshi Miyawaki (ORCID: https://orcid.org/0000-0001-6119-082X)
- Mitsuyoshi Utsugi
- Keiko Mitamura
- Daisuke Okuzaki (ORCID: https://orcid.org/0000-0002-4552-783X)
- Atsuya Narita
- Shuji Tohda (ORCID: https://orcid.org/0000-0002-2642-5459)
- Masanori Azuma (ORCID: https://orcid.org/0009-0008-6049-9161)
- Shigeki Fujitani (ORCID: https://orcid.org/0000-0001-6327-682X)
- Hisato Hiranuma
- Yoshihiro Kato (ORCID: https://orcid.org/0000-0001-9006-9551)
- Mumon Takita
- Noboru Takayanagi
- Kazunari Sonobe
- Yuji Yamamoto (ORCID: https://orcid.org/0000-0002-5489-5079)
- Toshihiro Kishikawa (ORCID: https://orcid.org/0000-0003-0590-3965)
- Yusuke Suzuki (ORCID: https://orcid.org/0000-0001-9357-4852)
- Kei Nishiyama (ORCID: https://orcid.org/0000-0003-3676-0135)
- Tadanaga Shimada (ORCID: https://orcid.org/0000-0002-0505-5145)
- Ryosuke Satomi
- Hajime Iwagoe
- Ayumi Yoshifuji (ORCID: https://orcid.org/0000-0001-8246-8675)
- Hiroyuki Muranaka
- Yuta Kono (ORCID: https://orcid.org/0000-0002-4098-496X)
- Sohei Nakayama (ORCID: https://orcid.org/0000-0002-6487-0422)
- Mitsuhiro Yamada (ORCID: https://orcid.org/0000-0002-0832-1939)
- Yu Kusaka (ORCID: https://orcid.org/0000-0001-6884-8110)
- Kosuke Yoshida (ORCID: https://orcid.org/0000-0002-6683-5970)
- Yuki Haruta (ORCID: https://orcid.org/0000-0001-8591-3850)
- Teruaki Murakami
- Takayoshi Hyugaji
- Tadashi Manabe (ORCID: https://orcid.org/0000-0001-9891-5222)
- Kazuhisa Yoshiya
- Fumimaro Ito (ORCID: https://orcid.org/0000-0002-1868-6405)
- Hiroto Matsuse (ORCID: https://orcid.org/0000-0003-0242-5005)
- Yoko Naito
- Toshiyuki Kita (ORCID: https://orcid.org/0000-0001-6158-7683)
- Shunsuke Uno (ORCID: https://orcid.org/0000-0002-9223-6138)
- Mayumi Takeuchi (ORCID: https://orcid.org/0000-0001-8447-7620)
- Masaki Yamasaki
- Yohei Mikami (ORCID: https://orcid.org/0000-0001-5104-4415)
- Satoru Miyawaki (ORCID: https://orcid.org/0000-0001-6369-3391)
- Shuichi Yoshida
- Rino Ishihara (ORCID: https://orcid.org/0000-0002-1312-6732)
- Tetsuya Fukuta
- Yoshitaka Oyamada (ORCID: https://orcid.org/0000-0002-0035-1316)
- Toshiro Sato (ORCID: https://orcid.org/0000-0001-8353-8137)
- Yasunari Kaneyama
- Norio Kodaka (ORCID: https://orcid.org/0000-0003-1833-6832)
- Hirotaka Eguchi
- Motonao Ishikawa (ORCID: https://orcid.org/0000-0003-0914-7298)
- Shun Shibata (ORCID: https://orcid.org/0000-0002-9081-1370)
- Masayuki Kanai (ORCID: https://orcid.org/0000-0002-2057-7347)
- Osamu Narumoto
- Masahiro Kanai (ORCID: https://orcid.org/0000-0001-5165-4408)
- Tatsuhiko Naito (ORCID: https://orcid.org/0000-0002-2779-4600)
- Akira Umeda (ORCID: https://orcid.org/0000-0003-3115-9842)
- Yoshiyuki Ohira (ORCID: https://orcid.org/0000-0002-2606-3611)
- Shuko Mashimo
- Takeshi Osawa (ORCID: https://orcid.org/0000-0002-6657-7916)
- Masamichi Sato (ORCID: https://orcid.org/0000-0002-8375-4996)
- Minoru Takada
- Reina Hayashi
- Yasushi Makino
- Tomoya Sano (ORCID: https://orcid.org/0000-0002-6359-5676)
- Nobuharu Ooshima
- Hiroshi Ono (ORCID: https://orcid.org/0000-0002-7617-8986)
- Kazuya Ichikado (ORCID: https://orcid.org/0000-0002-4840-2450)
- Suguru Ueda
- Takashige Kuraki
- Yoshiaki Tanaka (ORCID: https://orcid.org/0000-0003-0073-869X)
- Takeru Kashiwada
- Sawako Arai
- Naoki Miyazawa (ORCID: https://orcid.org/0000-0003-2983-7106)
- Baku Oyama
- Akihiro Ito (ORCID: https://orcid.org/0000-0001-7224-1100)
- Takehiro Izumo (ORCID: https://orcid.org/0000-0002-9052-0063)
- Yutaka Kozu (ORCID: https://orcid.org/0000-0003-4472-3625)
- Shuhei Yamada (ORCID: https://orcid.org/0000-0002-5734-9620)
- Yu Kasamatsu (ORCID: https://orcid.org/0000-0001-5675-2488)
- Shinji Ogura (ORCID: https://orcid.org/0000-0001-7686-6001)
- Akinori Kimura (ORCID: https://orcid.org/0000-0002-4933-2132)
- Kenichi Arakawa
- Masato Shinoki
- Yoko Shibata (ORCID: https://orcid.org/0000-0003-1794-0026)
- Tomonori Sato (ORCID: https://orcid.org/0000-0001-5659-6809)
- Takehiko Ohba (ORCID: https://orcid.org/0000-0002-2312-5688)
- Yuichi Maeda (ORCID: https://orcid.org/0000-0002-6831-8205)
- Kota Hoshino (ORCID: https://orcid.org/0000-0003-4482-109X)
- Yukihiro Yoshimura (ORCID: https://orcid.org/0000-0002-5046-7819)
- Taku Oshima (ORCID: https://orcid.org/0000-0002-3868-8272)
- Tomohiro Adachi
- Tomoki Nagasaka
- Mari Tone (ORCID: https://orcid.org/0000-0002-8230-0757)
- Yuko Kurihara
- Hiroshi Takahashi (ORCID: https://orcid.org/0000-0001-8410-0508)
- Yoshinori Tanino (ORCID: https://orcid.org/0000-0003-2384-601X)
- Ken Arimura (ORCID: https://orcid.org/0000-0002-7934-533X)
- Keisuke Onoi
- Takafumi Ueno (ORCID: https://orcid.org/0000-0001-9219-0726)
- Yutaro Kaneko
- Takemasa Matsumoto
- Yusuke Kawamura (ORCID: https://orcid.org/0000-0001-5021-1613)
- Hajime Sasano (ORCID: https://orcid.org/0000-0002-5200-4252)
- Sumiko Kohashi
- Hisatoshi Sugiura (ORCID: https://orcid.org/0000-0002-4335-7048)
- Fuminori Sugihara (ORCID: https://orcid.org/0000-0002-6228-4593)
- Atsushi Kumanogoh (ORCID: https://orcid.org/0000-0003-4749-7117)
- Hirofumi Kamata (ORCID: https://orcid.org/0000-0002-1807-5911)
- Shunichiro Konishi
- Hideyasu Sugimoto
- Takashi Inoue (ORCID: https://orcid.org/0000-0002-9672-2117)
- Takuya Inoue (ORCID: https://orcid.org/0000-0002-8824-1209)
- Satoko Hanada
- Taka‐aki Nakada (ORCID: https://orcid.org/0000-0002-4480-556X)
- Masao Hagihara (ORCID: https://orcid.org/0000-0002-7143-4813)
- Tomoya Tateishi (ORCID: https://orcid.org/0000-0001-5402-3185)
- Hiroko Watanabe (ORCID: https://orcid.org/0000-0001-6700-627X)
- Kazuhide Ohta (ORCID: https://orcid.org/0000-0001-9880-9163)
- Takashi Kagaya (ORCID: https://orcid.org/0000-0003-0819-632X)
- Kenji Takano
- Shigenari Nukaga (ORCID: https://orcid.org/0000-0003-4136-2879)
- Chihiro Tani Sassa
- Koji Murakami (ORCID: https://orcid.org/0000-0002-3745-4650)
- Hitoshi Sasano
- Atsushi Sueyoshi
- Takayuki Niitsu (ORCID: https://orcid.org/0000-0003-4280-3074)
- Yoshinori Fukui (ORCID: https://orcid.org/0000-0003-2335-8745)
- Toshikatsu Sado
- Akihiro Ono
- Masafumi Shimoda (ORCID: https://orcid.org/0000-0002-2465-0118)
- Hidefumi Koh
- Norihito Omote (ORCID: https://orcid.org/0000-0002-2637-0814)
- Isamu Kamimaki
- Yusuke Chihara (ORCID: https://orcid.org/0000-0002-7533-844X)
- Takahito M. Miyake (ORCID: https://orcid.org/0000-0001-6540-3220)
- Noah Sasa (ORCID: https://orcid.org/0009-0008-1517-6259)
- Hiroko Okabayashi (ORCID: https://orcid.org/0000-0002-1404-6830)
- Etsuko Tagaya (ORCID: https://orcid.org/0009-0002-0393-8822)
- Haruhi Takagi
- Yoichiro Kamatani (ORCID: https://orcid.org/0000-0001-8748-5597)
- Yasunari Miyazaki (ORCID: https://orcid.org/0000-0002-9073-9815)
- Shuhei Azekawa (ORCID: https://orcid.org/0000-0001-5538-6324)
- Naoki Hasegawa (ORCID: https://orcid.org/0000-0003-0717-7450)
- Toshio Odani
- Yoshinao Ono
- Albert Tenesa (ORCID: https://orcid.org/0000-0003-4884-4475)
- Aki Ogawa
- Yasuko Fuchimoto
- Masatoshi Miyazaki
- Eigo Shimizu (ORCID: https://orcid.org/0000-0002-2486-2321)
- N. Môri (ORCID: https://orcid.org/0000-0002-1433-0276)
- Hirayasu Kai (ORCID: https://orcid.org/0000-0002-4486-819X)
- Fumitake Saito
- Daiki Morikawa
- Takanori Kanai∥ (ORCID: https://orcid.org/0000-0002-1466-4532)
- Norihiko Takemoto (ORCID: https://orcid.org/0000-0003-1285-9667)
- Hiroto Kishi
- Kazuto Ito (ORCID: https://orcid.org/0000-0002-3735-2769)
- Ryunosuke Saiki (ORCID: https://orcid.org/0000-0001-6984-7187)
- Makoto Masuda (ORCID: https://orcid.org/0000-0003-2575-4506)
- Makoto Ishii (ORCID: https://orcid.org/0000-0003-4396-1664)
- Masaomi Yamamoto
- Keigo Kobayashi (ORCID: https://orcid.org/0000-0003-0609-9438)
- Shinichi Namba (ORCID: https://orcid.org/0000-0002-7486-3146)
- Yuji Hiramatsu (ORCID: https://orcid.org/0000-0003-4323-1098)
- Nobuyasu Awano (ORCID: https://orcid.org/0000-0002-1438-4880)
- Keita Masuzawa (ORCID: https://orcid.org/0000-0002-0549-8966)
- Shinnosuke Ikemura (ORCID: https://orcid.org/0000-0002-0022-7307)
- Takeshi Takahashi (ORCID: https://orcid.org/0000-0003-3971-3211)
- Tomohiro Matsunaga
- Yoshifumi Kimizuka (ORCID: https://orcid.org/0000-0002-4026-7506)
- Reiko Taki
- Katsushi Tokunaga (ORCID: https://orcid.org/0000-0001-5501-0503)
- Ai Nakamura (ORCID: https://orcid.org/0000-0001-7280-1796)
- Ai Tada
- Yoshikazu Mutoh (ORCID: https://orcid.org/0000-0002-7368-3004)
- Moritoki Egi (ORCID: https://orcid.org/0000-0002-0099-3060)
- Koji Okudela (ORCID: https://orcid.org/0000-0002-7525-4051)
- Aya Wakabayashi (ORCID: https://orcid.org/0000-0002-3489-2970)
- Ryousuke Aoki (ORCID: https://orcid.org/0000-0002-2330-9225)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Ho Lee (ORCID: https://orcid.org/0000-0002-0426-2281)
- Masatoshi Kawana (ORCID: https://orcid.org/0000-0003-0882-7347)
- Makoto Hiki
- Hiroyuki Minemura (ORCID: https://orcid.org/0000-0001-8710-1960)
- Takahiro Fukui (ORCID: https://orcid.org/0000-0002-3908-3726)
- Yasuhiko Yamano (ORCID: https://orcid.org/0000-0002-7779-9215)
- Sho Ota
- Keiko Wakahara (ORCID: https://orcid.org/0000-0001-7281-6760)
- Ryuji Koike (ORCID: https://orcid.org/0000-0001-5647-8159)
- Hiroshi Saito (ORCID: https://orcid.org/0000-0002-3338-478X)
- Katsunori Masaki (ORCID: https://orcid.org/0000-0003-0909-9409)
- Kazuhiko Katayama (ORCID: https://orcid.org/0000-0002-7692-1151)
- Munehisa Fukushima (ORCID: https://orcid.org/0000-0001-9785-8166)
- Hiroyuki Kokuto
- Tatsuhiko Anzai (ORCID: https://orcid.org/0000-0003-1073-2996)
- Masahiro Harada (ORCID: https://orcid.org/0000-0002-0162-5390)
- Soichiro Ueda (ORCID: https://orcid.org/0000-0001-9004-4688)
- Kosaku Nanki (ORCID: https://orcid.org/0000-0003-4232-0523)
- Akira Igarashi (ORCID: https://orcid.org/0000-0001-8892-7772)
- Haruhiko Kishima (ORCID: https://orcid.org/0000-0002-9041-2337)
- Naoya Hida (ORCID: https://orcid.org/0000-0003-4343-7504)
- Takahiro Tsuburai (ORCID: https://orcid.org/0000-0003-1968-1806)
- Youngjune Bhak (ORCID: https://orcid.org/0000-0002-9273-6984)
- Naoyuki Kuse
- Yoji Sagiya
- Keiko Kan‐o (ORCID: https://orcid.org/0000-0002-7736-588X)
- Mitsuru Motegi (ORCID: https://orcid.org/0000-0001-9030-2050)
- Hidenori Inohara (ORCID: https://orcid.org/0000-0003-4473-1203)
- Shohei Makino
- Masahiro Seike (ORCID: https://orcid.org/0000-0002-1572-5472)
- Hidenori Kanda
- Koichi Nishi (ORCID: https://orcid.org/0000-0003-4552-4310)
- Rie Baba (ORCID: https://orcid.org/0000-0002-8255-1978)
- Yoshihiko Nakamura (ORCID: https://orcid.org/0000-0002-2297-2885)
- Mariko Terashima
- Sonoko Harada (ORCID: https://orcid.org/0000-0002-3857-2624)
- Yuichi Adachi (ORCID: https://orcid.org/0000-0002-8867-3191)
- Hideki Terai (ORCID: https://orcid.org/0000-0002-1118-1930)
- Tomoki Kimura (ORCID: https://orcid.org/0000-0001-9745-3329)
- Satoshi Fuke
- Kota Murohashi (ORCID: https://orcid.org/0000-0002-2637-8218)
- Hirohito Sano (ORCID: https://orcid.org/0000-0003-2285-7577)
- Yuji Uchimura (ORCID: https://orcid.org/0000-0002-1645-466X)
- Ayako Takuwa
- Akihiko Tanaka (ORCID: https://orcid.org/0000-0003-3771-486X)
- Yukiko Nakajima (ORCID: https://orcid.org/0000-0003-4039-3593)
- Kenta Nishiyama (ORCID: https://orcid.org/0000-0003-4987-9952)
- Shinichi Hayashi (ORCID: https://orcid.org/0000-0002-1673-3853)
- Shuhei Sakakibara (ORCID: https://orcid.org/0000-0003-3157-5870)
- Shozo Yoshida (ORCID: https://orcid.org/0000-0002-3778-0560)
- Sae Wada
- Atsuho Morita (ORCID: https://orcid.org/0000-0001-5859-0304)
- Hiroshi Nishihara (ORCID: https://orcid.org/0000-0002-5460-8703)
- Tsuyoshi Oguma (ORCID: https://orcid.org/0000-0001-5086-9407)
- Ryuya Edahiro (ORCID: https://orcid.org/0000-0001-5009-6408)
- Takashi Yoshiyama (ORCID: https://orcid.org/0000-0002-7278-8816)
- Reiko Sado
- Shuhei Maruyama (ORCID: https://orcid.org/0000-0003-2491-2728)
- Genta Nagao
- Shinichi Ogawa (ORCID: https://orcid.org/0000-0002-7416-0926)
- Hiroki Kabata (ORCID: https://orcid.org/0000-0001-8853-6149)
- Akihiko Kawana
- Takayuki Honda (ORCID: https://orcid.org/0000-0002-1628-0698)
- Yoshifumi Uwamino (ORCID: https://orcid.org/0000-0001-9398-9599)
- Yuko Komase (ORCID: https://orcid.org/0000-0001-5042-8476)
- Kota Ishioka (ORCID: https://orcid.org/0000-0003-1652-1436)
- Chihiro Nakano (ORCID: https://orcid.org/0000-0001-6565-3289)
- Kazuki Niwa (ORCID: https://orcid.org/0000-0002-3367-3127)
- Saeko Takahashi (ORCID: https://orcid.org/0000-0002-5490-4203)
- Yuma Matsui
- Ryohei Suematsu (ORCID: https://orcid.org/0000-0002-5038-874X)
- James B. Wing (ORCID: https://orcid.org/0000-0002-3462-1003)
- Yoko Sato
- Tomomi Takano (ORCID: https://orcid.org/0000-0002-3468-0708)
- Takanori Asakura (ORCID: https://orcid.org/0000-0003-3122-6937)
- Norihiro Harada (ORCID: https://orcid.org/0000-0002-0962-5731)
- Satoru Hashimoto (ORCID: https://orcid.org/0000-0002-6726-9966)
- Ichiro Nakachi (ORCID: https://orcid.org/0000-0002-3930-9318)
- Noriyuki Kijima (ORCID: https://orcid.org/0000-0003-2103-1909)
- Syuji Kanayama
- Shin Ohta (ORCID: https://orcid.org/0000-0001-8744-6096)
- Yoshihisa Tokunaga
- Ken Suzuki (ORCID: https://orcid.org/0000-0003-1065-3593)
- Sho Uchida (ORCID: https://orcid.org/0000-0002-0767-3561)
- Nobukazu Fujimoto (ORCID: https://orcid.org/0000-0002-4516-0433)
- Kensuke Kanaoka (ORCID: https://orcid.org/0000-0002-1266-7043)
- Hideo Ogata
- Takefumi Nikaido (ORCID: https://orcid.org/0009-0000-6580-5262)
- Yuya Ueno
- Akifumi Endo (ORCID: https://orcid.org/0000-0002-8788-4042)
- Akiyoshi Nakayama (ORCID: https://orcid.org/0000-0002-6654-0726)
- Satoru Beppu (ORCID: https://orcid.org/0000-0002-1434-5697)
- Takatoshi Enomoto (ORCID: https://orcid.org/0000-0002-1771-6684)
- Kotoe Katayama (ORCID: https://orcid.org/0000-0002-3966-1231)
- Naozumi Hashimoto (ORCID: https://orcid.org/0000-0003-2337-629X)
- Junko Kagyo
- Yoshihiro Eriguchi (ORCID: https://orcid.org/0000-0002-5803-230X)
- Yoshito Takeda (ORCID: https://orcid.org/0000-0003-2905-6537)
- Yasutaka Fukui
- Fukuki Saito
- Reina Hara (ORCID: https://orcid.org/0000-0001-7013-4328)
- Junichi Ochi
- Yasushi Nakamori
- Koichiro Matsumoto (ORCID: https://orcid.org/0000-0003-2242-8131)
- Takayuki Shibusawa
- Takuya Hashino
- Kodai Kawamura (ORCID: https://orcid.org/0000-0002-6981-0648)
- Yasuhito Nannya (ORCID: https://orcid.org/0000-0002-6526-0992)
- Tomoo Ishii (ORCID: https://orcid.org/0000-0002-7217-7791)
- Kazuya Miyagawa (ORCID: https://orcid.org/0000-0002-7633-5427)
- Miki Kawada
- Shigehiro Hagiwara
- Namiki Izumi (ORCID: https://orcid.org/0000-0002-0055-8229)
- Yoichi Kobayashi (ORCID: https://orcid.org/0000-0002-8474-0625)
- Hidetoshi Kawashima (ORCID: https://orcid.org/0000-0003-1163-5389)
- Shigeru Chiba (ORCID: https://orcid.org/0000-0001-7803-7338)
- Toshio Naito (ORCID: https://orcid.org/0000-0003-1646-9930)
- Mizuki Kuramochi
- Hiroyuki Hayashi (ORCID: https://orcid.org/0000-0002-7590-6419)
- Tatsuya Yamashita
- Isano Hase (ORCID: https://orcid.org/0000-0003-3563-0136)
- Hisako Sageshima
- Daiki Wada (ORCID: https://orcid.org/0000-0002-3404-9924)
- Akane Kamiya (ORCID: https://orcid.org/0000-0002-2285-3974)
- Kazuma Yagi (ORCID: https://orcid.org/0000-0002-9752-9589)
- Hirotaka Matsuo (ORCID: https://orcid.org/0000-0003-4302-8719)
- Tomohisa Shoko (ORCID: https://orcid.org/0000-0002-3866-1897)
- Takanori Hasegawa (ORCID: https://orcid.org/0000-0001-7251-9950)
- Masatoshi Shimo
- Naoya Ichimura
- Yoshiyuki Sekikawa
- Hiroaki Baba (ORCID: https://orcid.org/0000-0001-5487-6698)
- Morio Nakamura (ORCID: https://orcid.org/0000-0002-0140-6155)
- Masatoshi Takagaki (ORCID: https://orcid.org/0000-0001-7100-8366)
- Yoko Ito (ORCID: https://orcid.org/0000-0002-7791-1967)
- Daisuke Arai (ORCID: https://orcid.org/0000-0002-9046-6300)
- Akinori Kanai (ORCID: https://orcid.org/0000-0003-1555-6768)
- Qingbo S. Wang (ORCID: https://orcid.org/0000-0002-9110-5830)
- Koichi Matsuda
- Koichi Fukunaga (ORCID: https://orcid.org/0000-0001-7460-1990)
- Saori Amiya
- Yoshimi Noda
- Reoto Takei (ORCID: https://orcid.org/0000-0003-1698-2304)
- Yasuhiro Gon (ORCID: https://orcid.org/0000-0003-0514-3054)
- Tomoya Tsuchida (ORCID: https://orcid.org/0000-0002-8517-3941)
- Masaru Amishima (ORCID: https://orcid.org/0000-0001-5010-5378)
- Yoshihiro Hirai
- Hatsuyo Takaoka
- Hiromu Tanaka (ORCID: https://orcid.org/0000-0002-5299-3978)
- Takayuki Ogura (ORCID: https://orcid.org/0000-0002-2525-4985)
- Yasuo Shichinohe
- Hideya Kitamura (ORCID: https://orcid.org/0000-0002-5800-1175)
- Yosuke Omae (ORCID: https://orcid.org/0000-0001-9978-4869)
- Yoshiaki Inoue (ORCID: https://orcid.org/0000-0001-6407-1965)
- Junko Hamamoto (ORCID: https://orcid.org/0000-0002-8054-0124)
- Mitsuaki Kojima (ORCID: https://orcid.org/0000-0001-8630-1469)
- Masakiyo Yatomi (ORCID: https://orcid.org/0000-0001-6840-515X)
- Kazunori Nakamura (ORCID: https://orcid.org/0000-0001-8386-3052)
- Takeshi Oshio
- Koichiro Asano (ORCID: https://orcid.org/0000-0002-9044-3061)
- Takayoshi Morita (ORCID: https://orcid.org/0000-0002-7111-9506)
- Yoshiya Oda
- Erin Macdonald-Dunlop (ORCID: https://orcid.org/0000-0001-6569-6086)
- Tomoyasu Nishimura (ORCID: https://orcid.org/0000-0001-9662-5694)
- Keisuke Shinozuka
- Taisuke Isono (ORCID: https://orcid.org/0000-0002-2803-8049)
- Yohei Funatsu (ORCID: https://orcid.org/0000-0002-0474-2672)
- Sumito Inoue (ORCID: https://orcid.org/0000-0002-1817-9761)
- Yuta Yamaguchi (ORCID: https://orcid.org/0000-0002-8314-9294)
- Takao Mochimaru (ORCID: https://orcid.org/0000-0002-1505-6651)
- Shuhei Kawabata
- Hiroyasu Ishikura (ORCID: https://orcid.org/0000-0002-4862-5646)
- Koutaro Yokote (ORCID: https://orcid.org/0000-0003-3033-4813)
- Kentaro Hayashi (ORCID: https://orcid.org/0000-0002-2936-9544)
- Ryota Kikuchi (ORCID: https://orcid.org/0000-0002-0854-3494)
- Yuta Matsubara (ORCID: https://orcid.org/0000-0002-8714-6357)
- Kunihiro Yamagata (ORCID: https://orcid.org/0000-0002-7407-0410)
- Hiromu Iwamura
- Shunsuke Maeda
- Meiko Takahashi (ORCID: https://orcid.org/0000-0002-8344-5472)
- Kazuhisa Takahashi (ORCID: https://orcid.org/0000-0001-5749-4118)
- Hiroshi Morisaki (ORCID: https://orcid.org/0000-0002-2790-2093)
- Takashi Ishiguro (ORCID: https://orcid.org/0000-0001-6004-1769)
- Hidenori Takahashi (ORCID: https://orcid.org/0000-0001-9781-258X)
- Nobuhiro Kodama
- Toshitaka Maeno (ORCID: https://orcid.org/0000-0002-8428-1617)
- Nozomu Kimura (ORCID: https://orcid.org/0009-0002-4596-0964)
- Kazunori Tomono (ORCID: https://orcid.org/0000-0002-3424-472X)
- Ken Ohta (ORCID: https://orcid.org/0000-0001-9734-4579)
- Tomonori Imamura
- Kazumi Nishio (ORCID: https://orcid.org/0000-0003-2103-654X)
- Chiaki Hosoda (ORCID: https://orcid.org/0000-0002-8337-2285)
- Toru Yoshida (ORCID: https://orcid.org/0000-0001-9341-9887)
- Satoshi Okamori (ORCID: https://orcid.org/0000-0002-4562-1455)
- Tetsuo Shimizu (ORCID: https://orcid.org/0000-0003-3405-9652)
- Kana Sasaki (ORCID: https://orcid.org/0009-0007-7508-8528)
- Makoto Yamamoto (ORCID: https://orcid.org/0000-0001-7844-331X)
- Mitsuru Odate
- Takatomo Hirouchi
- Eri Hagiwara (ORCID: https://orcid.org/0000-0003-0079-7462)
- Minoru Inomata (ORCID: https://orcid.org/0000-0003-4149-9779)
- Takashi Ogura (ORCID: https://orcid.org/0000-0002-7445-270X)
- Hisato Shimada
- Yunye He (ORCID: https://orcid.org/0000-0001-8581-7826)
- Tomoki Kuge (ORCID: https://orcid.org/0000-0002-9787-1659)
- Masaru Nishitsuji
- Susumu Isogai (ORCID: https://orcid.org/0000-0002-1835-2528)
- Yoshiteru Tominaga
- Shotaro Chubachi (ORCID: https://orcid.org/0000-0002-5046-3762)
- Yuya Shirai (ORCID: https://orcid.org/0000-0002-0518-9020)
- Haruhiko Hirata (ORCID: https://orcid.org/0000-0002-1134-7283)
- Hiroki Tateno (ORCID: https://orcid.org/0000-0003-3061-1489)
- Hiroki Nakatsumi
- Masaki Okamoto (ORCID: https://orcid.org/0000-0002-9298-3504)
- Takahito Fukusumi (ORCID: https://orcid.org/0009-0002-1857-7548)
- Ryuzo Abe (ORCID: https://orcid.org/0000-0003-0888-0420)
- Kazue Fujita
- Tadao Nagasaki (ORCID: https://orcid.org/0000-0002-3231-7841)
- Satoru Miyano (ORCID: https://orcid.org/0000-0002-1753-6616)
- Yoshimune Miyazaki
- Ryusuke Anan
- Tomouki Ogata
- Yuichiro Kitagawa (ORCID: https://orcid.org/0009-0004-9965-8810)
- Yasuhiro Kato (ORCID: https://orcid.org/0000-0002-4050-2350)
- Junichi Sasaki (ORCID: https://orcid.org/0000-0002-5190-8524)
- Arihiko Kanehiro (ORCID: https://orcid.org/0000-0003-0160-9662)
- Hironori Sagara (ORCID: https://orcid.org/0000-0003-2376-1606)
- Seiya Imoto (ORCID: https://orcid.org/0000-0002-2989-308X)
- Sayoko Ishihara
- Ryosuke Arai
- Mizuha Hashiguchi (ORCID: https://orcid.org/0000-0002-4698-1655)
- Akiko Yonekawa
- Kyuto Sonehara (ORCID: https://orcid.org/0000-0002-4536-1761)
- Naota Kuwahara
- Takayuki Shiroyama (ORCID: https://orcid.org/0000-0002-2816-9428)
- Yu‐Chen Liu (ORCID: https://orcid.org/0000-0002-2750-0182)
- Tomoyuki Uchida
- Tomoyuki Kimura
- Fumihiko Matsuda
- Kunihiko Takahashi (ORCID: https://orcid.org/0000-0003-2387-7772)
- Yasushi Nakano
- Hiroki Watanabe (ORCID: https://orcid.org/0000-0002-1892-9788)
- Toru Tanaka (ORCID: https://orcid.org/0000-0002-1054-9211)
- Yuko Kitagawa (ORCID: https://orcid.org/0000-0002-0271-5670)
- Takao Imai (ORCID: https://orcid.org/0000-0002-1686-6787)
- Yasushi Matsushita (ORCID: https://orcid.org/0000-0002-9162-8973)
- J. Suzuki (ORCID: https://orcid.org/0000-0001-6816-8123)
- Yuichiro Yamada (ORCID: https://orcid.org/0000-0003-1623-0815)
- Yuki Sato (ORCID: https://orcid.org/0000-0002-8986-8388)
- Toshihiro Sakurai (ORCID: https://orcid.org/0000-0002-6634-9913)
- Shoji Suzuki (ORCID: https://orcid.org/0000-0003-1760-1024)
- Yoshinori Hasegawa (ORCID: https://orcid.org/0000-0003-3841-4631)
- Kazuhiko Fujii (ORCID: https://orcid.org/0000-0003-3711-256X)
- Shinji Abe (ORCID: https://orcid.org/0000-0003-0949-4601)
- Jun Nakajima (ORCID: https://orcid.org/0000-0003-1174-0816)
- Takashi Nishida (ORCID: https://orcid.org/0000-0001-8220-2738)
- Akira Ando (ORCID: https://orcid.org/0000-0002-6762-039X)
- Tetsuya Ueda (ORCID: https://orcid.org/0000-0003-2933-9983)
- Mai Takahashi (ORCID: https://orcid.org/0000-0002-3835-2939)
- Yoshinobu Saito (ORCID: https://orcid.org/0000-0001-9630-8066)
- Kenichiro Takahashi (ORCID: https://orcid.org/0000-0002-3522-9740)
- Masafumi Watanabe (ORCID: https://orcid.org/0000-0002-8672-7483)
- Toshiyuki Hirano (ORCID: https://orcid.org/0000-0003-1856-8385)
- Yutaka Suzuki
- Ryuichi Saito
- Yuko Harada
- Tomoya Baba
- Yasuhiro Kimura (ORCID: https://orcid.org/0009-0002-7607-6450)
- Anders Mälarstig
- Satoru Sakagami
- Natsuo Tachikawa
- Emmy Yanagita
- Ken Ueda
- Kiyoshi Komuta
- Masanori Nishikawa (ORCID: https://orcid.org/0000-0003-4253-5153)
- Satoshi Hagimoto
- Vasilis Raptis (ORCID: https://orcid.org/0009-0004-2579-0421)
- Kazuyoshi Watanabe
- Shoichiro Ishihara
- C Watanabe (ORCID: https://orcid.org/0000-0001-9293-7164)
- Hirohisa Horinouchi (ORCID: https://orcid.org/0000-0002-9131-3357)
- Yoichiro Noguchi
- Takuro Nii
- Yoshinori Yasui
- Yuki Togashi
- Shuichiro Matsumoto
- Ken-ichi Yamamoto
- Takeshi Hattori
- Shinji Ozaki
- Mayuko Tani
- Ryuichi Sato (ORCID: https://orcid.org/0009-0000-1676-8784)
- Nobuyuki Hizawa
- Yoji Nagasaki
- Kiyoshi Koshida
- Kaoru Nagata
- Midori Yoneda
- Tomoko Nakanishi
- Shôichi Ihara
- Motoyuki Suzuki
- Masumi Ai (ORCID: https://orcid.org/0000-0003-1950-165X)
- Tomoyuki Yoshihara (ORCID: https://orcid.org/0009-0004-0766-7315)
- Tetsuya Shiomi
- Satoru Fukuyama
- Akiko Fujiwara
- Junko Maruyama (ORCID: https://orcid.org/0000-0002-4853-6002)
- Takenori Okada
- Hideaki Nagai
Institutions
- Nihon University (JP)
- Kurume University (JP)
- Yamagata University (JP)
- Tokyo Institute of Technology (JP)
- SHOWA Medical University (JP)
- Tokyo Medical and Dental University (JP)
- Kansai Medical University (JP)
- Toho University (JP)
- Fukushima Medical University (JP)
- Tokai University (JP)
- Roslin Institute (GB)
- Kyushu University (JP)
- Harvard University (US)
- University of Tsukuba (JP)
- Chiba University (JP)
- St. Marianna University School of Medicine (JP)
- Gunma University (JP)
- Tohoku University (JP)
- Keio University (JP)
- Japan Society for the Promotion of Science (JP)
- Kyoto University (JP)
- Fujisawa City Hospital (JP)
- Saitama Prefecture (JP)
- NTT Medical Center (JP)
- Japan Agency for Medical Research and Development (JP)
- Karolinska Institutet (SE)
- Kyoto Medical Center (JP)
- National Kyushu Medical Center (JP)
- Himeji University (JP)
- Fukuoka University (JP)
- Juntendo University (JP)
- Kyoto Prefectural University of Medicine (JP)
- Kumamoto City Hospital (JP)
- Kanazawa Medical Center (JP)
- Pfizer (Sweden) (SE)
- Fukuoka University Hospital (JP)
- Toho University Ohashi Medical Center (JP)
- National Center for Global Health and Medicine (JP)
- Tokyo Medical Center (JP)
- Saiseikai Kumamoto Hospital (JP)
- Ome Municipal General Hospital (JP)
- Yokohama City Seibu Hospital (JP)
- Fukuoka Tokushukai Hospital (JP)
- National Hospital Organization Hokkaido Medical Center (JP)
- Japanese Red Cross Medical Center (JP)
- Suita Tokushukai Hospital (JP)
- Keio University Hospital (JP)
- Eiju General Hospital (JP)
- Osaka Police Hospital (JP)
- Tokyo Medical University Hospital (JP)
- Kansai Rosai Hospital (JP)
- Kawasaki Municipal Hospital (JP)
- Ishikawa Prefectural Central Hospital (JP)
- Social Welfare Organization Saiseikai Imperial Gift Foundation (JP)
- JA Toride Medical Center (JP)
- Sapporo Kosei General Hospital (JP)
- Kansai Electric Power Hospital (JP)
- Saiseikai Utsunomiya hospital (JP)
- Himeji Medical Center (JP)
- Saiseikai Central Hospital (JP)
- Aichi Cancer Center (JP)
- Shizuoka General Hospital (JP)
- Tokyo Women's Medical University Adachi Medical Center (JP)
- Tokyo Medical University Ibaraki Medical Center (JP)
- Saitama Municipal Hospital (JP)
- Japan Organization of Occupational Health and Safety (JP)
- Yokohama Municipal Citizen's Hospital (JP)
- Tokyo Women's Medical University (JP)
- Saiseikai Nakatsu Hospital (JP)
- National Hospital Organization (JP)
- Tsukuba Medical Center Hospital (JP)
- Matsumoto City Hospital (JP)
- Tachikawa Hospital (JP)
- keiyu Hospital (JP)
- Kanagawa Cardiovascular and Respiratory Center (JP)
- Okayama Rosai Hospital (JP)
- Toyohashi Municipal Hospital (JP)
- Sapporo City General Hospital (JP)
- Musashino Red Cross Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Fukujuji Hospital (JP)
- Kitasato Institute Hospital (JP)
- Osaka University Hospital (JP)
- Tokyo National Hospital (JP)
- Social Insurance Saitama Chuo Hospital (JP)
- Institute of Genetics and Cancer (GB)
- Tosei General Hospital (JP)
- Tokyo Metropolitan Police Hospital (JP)
- Kanazawa Hospital (JP)
- Saiseikai Ibaraki Hospital (JP)
- Tokyo Medical and Dental University Hospital (JP)
- Institute for International Studies and Training (JP)
- Kumamoto Medical Center (JP)
- Gifu University (JP)
- National Hospital Organization Saitama Hospital
- National Defense Medical College (JP)
- Nagoya University (JP)
- Kitasato University (JP)
- Kobe University (JP)
- Niigata University (JP)
- The University of Tokyo (JP)
- International University of Health and Welfare (JP)
- Nippon Medical School (JP)
- Yokohama City University (JP)
- The University of Osaka (JP)
- University of Edinburgh (GB)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1038/s41598-025-10031-z
- Citations
- 1
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Japan Agency for Medical Research and Development
- Canadian Institute of Steel Construction
- National Institute for Health and Care Research
- Department of Health and Social Care
- Kela
- Ministry of Health, Labour and Welfare
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology
- Precursory Research for Embryonic Science and Technology
- Moonshot Research and Development Program