Identification and replication of sex-dimorphic protein quantitative trait loci across multiple ancestries and their associations with diseases
Abstract
Abstract 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.
Article Details
Authors (501)
Youngjune Bhak
Vasilis Raptis
Yunye He
Tomoko Nakanishi
Erin Macdonald-Dunlop
Yoji Sagiya
Takayuki Morisaki
Koichi Matsuda
Ryuya Edahiro
Tomomi Takano
Hiroshi Nishihara
Yuya Shirai
Kyuto Sonehara
Hiromu Tanaka
Shuhei Azekawa
Yohei Mikami
Ho Lee
Takanori Hasegawa
Koji Okudela
Daisuke Okuzaki
Daisuke Motooka
Masahiro Kanai
Tatsuhiko Naito
Kenichi Yamamoto
Qingbo S. Wang
Rino Ishihara
Yuta Matsubara
Junko Hamamoto
Hiroyuki Hayashi
Yukihiro Yoshimura
Natsuo Tachikawa
Emmy Yanagita
Takayoshi Hyugaji
Eigo Shimizu
Kotoe Katayama
Yasuhiro Kato
Takayoshi Morita
Kazuhisa Takahashi
Norihiro Harada
Toshio Naito
Makoto Hiki
Yasushi Matsushita
Haruhi Takagi
Ryousuke Aoki
Ai Nakamura
Sonoko Harada
Hitoshi Sasano
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
Kazumi Nishio
Tetsuya Ueda
Masanori Azuma
Ryuichi Saito
Toshikatsu Sado
Yoshimune Miyazaki
Ryuichi Sato
Yuki Haruta
Tadao Nagasaki
Yoshinori Yasui
Yoshinori Hasegawa
Yoshikazu Mutoh
Tomoki Kimura
Tomonori Sato
Reoto Takei
Satoshi Hagimoto
Yoichiro Noguchi
Yasuhiko Yamano
Hajime Sasano
Sho Ota
Yasushi Nakamori
Kazuhisa Yoshiya
Fukuki Saito
Tomoyuki Yoshihara
Daiki Wada
Hiromu Iwamura
Syuji Kanayama
Shuhei Maruyama
Takashi Yoshiyama
Ken Ohta
Hiroyuki Kokuto
Hideo Ogata
Yoshiaki Tanaka
Kenichi Arakawa
Masafumi Shimoda
Takeshi Osawa
Hiroki Tateno
Isano Hase
Shuichi Yoshida
Shoji Suzuki
Miki Kawada
Hirohisa Horinouchi
Fumitake Saito
Keiko Mitamura
Masao Hagihara
Junichi Ochi
Tomoyuki Uchida
Rie Baba
Daisuke Arai
Takayuki Ogura
Hidenori Takahashi
Shigehiro Hagiwara
Genta Nagao
Shunichiro Konishi
Ichiro Nakachi
Koji Murakami
Mitsuhiro Yamada
Hisatoshi Sugiura
Hirohito Sano
Shuichiro Matsumoto
Nozomu Kimura
Yoshinao Ono
Hiroaki Baba
Yusuke Suzuki
Sohei Nakayama
Keita Masuzawa
Shinichi Namba
Ken Suzuki
Yoko Naito
Yu-Chen Liu
Ayako Takuwa
Fuminori Sugihara
James B. Wing
Shuhei Sakakibara
Nobuyuki Hizawa
Takayuki Shiroyama
Satoru Miyawaki
Yusuke 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
Motoyuki Suzuki
Norihiko Takemoto
Hirotaka Eguchi
Takahito Fukusumi
Takao Imai
Munehisa Fukushima
Haruhiko Kishima
Hidenori Inohara
Kazunori Tomono
Kazuto Kato
Meiko Takahashi
Fumihiko Matsuda
Haruhiko Hirata
Yoshito Takeda
Hidefumi Koh
Tadashi Manabe
Yohei Funatsu
Fumimaro Ito
Takahiro Fukui
Keisuke Shinozuka
Sumiko Kohashi
Masatoshi Miyazaki
Tomohisa Shoko
Mitsuaki Kojima
Tomohiro Adachi
Motonao Ishikawa
Kenichiro Takahashi
Takashi Inoue
Toshiyuki Hirano
Keigo Kobayashi
Hatsuyo Takaoka
Kazuyoshi Watanabe
Naoki Miyazawa
Yasuhiro Kimura
Reiko Sado
Hideyasu Sugimoto
Akane Kamiya
Naota Kuwahara
Akiko Fujiwara
Tomohiro Matsunaga
Yoko Sato
Takenori Okada
Yoshihiro Hirai
Hidetoshi Kawashima
Atsuya Narita
Kazuki Niwa
Yoshiyuki Sekikawa
Koichi Nishi
Masaru Nishitsuji
Mayuko Tani
Junya Suzuki
Hiroki Nakatsumi
Takashi Ogura
Hideya Kitamura
Eri Hagiwara
Kota Murohashi
Hiroko Okabayashi
Takao Mochimaru
Shigenari Nukaga
Ryosuke Satomi
Yoshitaka Oyamada
Nobuaki Mori
Tomoya Baba
Yasutaka Fukui
Mitsuru Odate
Shuko Mashimo
Yasushi Makino
Kazuma Yagi
Mizuha Hashiguchi
Junko Kagyo
Tetsuya Shiomi
Satoshi Fuke
Hiroshi Saito
Tomoya Tsuchida
Shigeki Fujitani
Mumon Takita
Daiki Morikawa
Toru Yoshida
Takehiro Izumo
Minoru Inomata
Naoyuki Kuse
Nobuyasu Awano
Mari Tone
Akihiro Ito
Yoshihiko Nakamura
Kota Hoshino
Junichi Maruyama
Hiroyasu Ishikura
Tohru Takata
Toshio Odani
Masaru Amishima
Takeshi Hattori
Yasuo Shichinohe
Takashi Kagaya
Toshiyuki Kita
Kazuhide Ohta
Satoru Sakagami
Kiyoshi Koshida
Kentaro Hayashi
Tetsuo Shimizu
Yutaka Kozu
Hisato Hiranuma
Yasuhiro Gon
Namiki Izumi
Kaoru Nagata
Ken Ueda
Reiko Taki
Satoko Hanada
Kodai Kawamura
Kazuya Ichikado
Kenta Nishiyama
Hiroyuki Muranaka
Kazunori Nakamura
Naozumi Hashimoto
Keiko Wakahara
Sakamoto Koji
Norihito Omote
Akira Ando
Nobuhiro Kodama
Yasunari Kaneyama
Shunsuke Maeda
Takashige Kuraki
Takemasa Matsumoto
Koutaro Yokote
Taka-Aki Nakada
Ryuzo Abe
Taku Oshima
Tadanaga Shimada
Masahiro Harada
Takeshi Takahashi
Hiroshi Ono
Toshihiro Sakurai
Takayuki Shibusawa
Yoshifumi Kimizuka
Akihiko Kawana
Tomoya Sano
Chie Watanabe
Ryohei Suematsu
Hisako Sageshima
Ayumi Yoshifuji
Kazuto Ito
Saeko Takahashi
Kota Ishioka
Morio Nakamura
Makoto Masuda
Aya Wakabayashi
Hiroki Watanabe
Suguru Ueda
Masanori Nishikawa
Yusuke Chihara
Mayumi Takeuchi
Keisuke Onoi
Jun Shinozuka
Atsushi Sueyoshi
Yoji Nagasaki
Masaki Okamoto
Sayoko Ishihara
Masatoshi Shimo
Yoshihisa Tokunaga
Yu Kusaka
Takehiko Ohba
Susumu Isogai
Aki Ogawa
Takuya Inoue
Satoru Fukuyama
Yoshihiro Eriguchi
Akiko Yonekawa
Keiko Kan-o
Koichiro Matsumoto
Kensuke Kanaoka
Shoichi Ihara
Kiyoshi Komuta
Yoshiaki Inoue
Shigeru Chiba
Kunihiro Yamagata
Yuji Hiramatsu
Hirayasu Kai
Koichiro Asano
Tsuyoshi Oguma
Yoko Ito
Satoru Hashimoto
Masaki Yamasaki
Yu Kasamatsu
Yuko Komase
Naoya Hida
Takahiro Tsuburai
Baku Oyama
Minoru Takada
Hidenori Kanda
Yuichiro Kitagawa
Tetsuya Fukuta
Takahito Miyake
Shozo Yoshida
Shinji Ogura
Shinji Abe
Yuta Kono
Yuki Togashi
Hiroyuki Takoi
Ryota Kikuchi
Shinichi Ogawa
Tomouki Ogata
Shoichiro Ishihara
Arihiko Kanehiro
Shinji Ozaki
Yasuko Fuchimoto
Sae Wada
Nobukazu Fujimoto
Kei Nishiyama
Mariko Terashima
Satoru Beppu
Kosuke Yoshida
Osamu Narumoto
Hideaki Nagai
Nobuharu Ooshima
Mitsuru Motegi
Akira Umeda
Kazuya Miyagawa
Hisato Shimada
Mayu Endo
Yoshiyuki Ohira
Masafumi Watanabe
Sumito Inoue
Akira Igarashi
Masamichi Sato
Hironori Sagara
Akihiko Tanaka
Shin Ohta
Tomoyuki Kimura
Yoko Shibata
Yoshinori Tanino
Takefumi Nikaido
Hiroyuki Minemura
Yuki Sato
Yuichiro Yamada
Takuya Hashino
Masato Shinoki
Hajime Iwagoe
Hiroshi Takahashi
Kazuhiko Fujii
Hiroto Kishi
Masayuki Kanai
Tomonori Imamura
Tatsuya Yamashita
Masakiyo Yatomi
Toshitaka Maeno
Shinichi Hayashi
Mai Takahashi
Mizuki Kuramochi
Isamu Kamimaki
Yoshiteru Tominaga
Tomoo Ishii
Mitsuyoshi Utsugi
Akihiro Ono
Toru Tanaka
Takeru Kashiwada
Kazue Fujita
Yoshinobu Saito
Masahiro Seike
Hiroko Watanabe
Hiroto Matsuse
Norio Kodaka
Chihiro Nakano
Takeshi Oshio
Takatomo Hirouchi
Shohei Makino
Moritoki Egi
Yosuke Omae
Yasuhito Nannya
Takafumi Ueno
Kazuhiko Katayama
Masumi Ai
Yoshinori Fukui
Atsushi Kumanogoh
Toshiro Sato
Naoki Hasegawa
Katsushi Tokunaga
Makoto Ishii
Yuko Kitagawa
Akinori Kanai
Yutaka Suzuki
Yoshiya Oda
Yoichiro Kamatani
Ho Namkoong
Ryunosuke Saiki
Akinori Kimura
Ryuji Koike
Seishi Ogawa
Satoru Miyano
Seiya Imoto
Takanori Kanai
Koichi Fukunaga
Yukinori Okada
Anders Mälarstig
Albert Tenesa