Polygenic effects on the risk of Alzheimer’s disease in the Japanese population
Authors: Kikuchi Masataka , Miyashita Akinori , Hara Norikazu , Kasuga Kensaku , Saito Yuko , Murayama Shigeo , Kakita Akiyoshi , Akatsu Hiroyasu , Ozaki Kouichi , Niida Shumpei , Kuwano Ryozo , Iwatsubo Takeshi , Nakaya Akihiro , Ikeuchi Takeshi ,   the Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W. , Mason Sara S. , Albers Colleen S. , Knopman David , Johnson Kris , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Schneider Lon S. , Pawluczyk Sonia , Beccera Mauricio , Teodoro Liberty , Spann Bryan M. , Beckett Laurel , Green Robert C. , Morris John , Shaw Leslie M. , Ances Beau , Morris John C. , Carroll Maria , Creech Mary L. , Franklin Erin , Mintun Mark A. , Schneider Stacy , Oliver Angela , Kaye Jeffrey , Quinn Joseph , Silbert Lisa , Lind Betty , Carter Raina , Dolen Sara , Brewer James , Vanderswag Helen , Fleisher Adam , Heidebrink Judith L. , Lord Joanne L. , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Marson Daniel , Griffith Randall , Clark David , Geldmacher David , Brockington John , Roberson Erik , Love Marissa Natelson , Grossman Hillel , Mitsis Effie , Shah Raj C. , deToledo-Morrell Leyla , Duara Ranjan , Varon Daniel , Greig Maria T. , Roberts Peggy , Albert Marilyn , Onyike Chiadi , D’Agostino Daniel , Kielb Stephanie , Galvin James E. , Cerbone Brittany , Michel Christina A. , Pogorelec Dana M. , Rusinek Henry , de Leon Mony J. , Glodzik Lidia , De Santi Susan , Doraiswamy P. Murali , Petrella Jeffrey R. , Borges-Neto Salvador , Wong Terence Z. , Coleman Edward , Smith Charles D. , Jicha Greg , Hardy Peter , Sinha Partha , Oates Elizabeth , Conrad Gary , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc-Adams-Ortiz Catherine , Womack Kyle , Mathews Dana , Quiceno Mary , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Swerdlow Russell H. , Brooks William M. , Apostolova Liana , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Brosch Jared R. , Herring Scott , Hunt Cynthia , Tingus Kathleen , Woo Ellen , Silverman Daniel H. S. , Lu Po H. , Bartzokis George , Graff-Radford Neill R. , Parfitt Francine , Kendall Tracy , Johnson Heather , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Varma Pradeep , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging-Yuek Robin , Feldman Howard , Mudge Benita , Assaly Michele , Finger Elizabeth , Pasternack Stephen , Rachisky Irina , Trost Dick , Kertesz Andrew , Bernick Charles , Munic Donna , Mesulam Marek Marsel , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Sadowsky Carl , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Johnson Keith A. , Marshall Gad , Yesavage Jerome , Taylor Joy L. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan N. , Belden Christine M. , Jacobson Sandra A. , Sirrel Sherye A. , Kowall Neil , Killiany Ronald , Budson Andrew E. , Norbash Alexander , Johnson Patricia Lynn , Obisesan Thomas O. , Wolday Saba , Allard Joanne , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Carmichael Owen , Kittur Smita , Borrie Michael , Lee T.-Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Burke Anna , Trncic Nadira , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Scharre Douglas W. , Kataki Maria , Adeli Anahita , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Flashman Laura A. , Seltzer Marc , Hynes Mary L. , Santulli Robert B. , Sink Kaycee M. , Gordineer Leslie , Williamson Jeff D. , Garg Pradeep , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Perry David , Mintzer Jacobo , Spicer Kenneth , Bachman David , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Relkin Norman , Chaing Gloria , Lin Michael , Ravdin Lisa , Smith Amanda , Raj Balebail Ashok , Fargher Kristin ,   the Japanese Alzheimer’s Disease Neuroimaging Initiative, Asada Takashi , Arai Hiroyuki , Sugishita Morihiro , Matsuda Hiroshi , Sato Noriko , Sato Hajime , Ito Kengo , Kachi Teruhiko , Toba Kenji , Senda Michio , Ishii Kenji , Shimohama Shun , Saitoh Masaki , Yamauchi Rika , Hayashi Takashi , Takanami Chiyoko , Kobayashi Seiju , Nakano Norihito , Kanazawa Junichiro , Ando Takeshi , Hareyama Masato , Hatakenaka Masamitsu , Tsukamoto Eriko , Ochi Shinji , Shoji Mikio , Matsubara Etsuro , Kawarabayashi Takeshi , Wakasaya Yasuhito , Nakata Takashi , Nakahata Naoko , Ono Shuichi , Takai Yoshihiro , Takahashi Satoshi , Yonezawa Hisashi , Takahashi Junko , Kudoh Masako , Ueno Kuniko , Sakashita Hiromi , Watanabe Kuniko , Sasaki Makoto , Matsumura Yutaka , Hirata Yohsuke , Metoki Tsuyoshi , Hayakawa Susumu , Sato Yuichi , Takeda Masayuki , Sera Koichiro , Terasaki Kazunori , Sasaki Toshiaki , Saitoh Yoshihiro , Goto Shoko , Nagata Ken , Maeda Tetsuya , Kondoh Yasushi , Yamazaki Takashi , Takano Daiki , Miyata Mio , Komatsu Hiromi , Watanabe Mayumi , Sinoda Tomomi , Muraoka Rena , Kikuchi Kayoko , Ito Hitomi , Sato Aki , Kinoshita Toshibumi , Toyoshima Hideyo , Sato Kaoru , Sugawara Shigeki , Ito Isao , Kumagai Fumiko , Furukawa Katsutoshi , Waragai Masaaki , Tomita Naoki , Ootsuki Mari , Sugawara Katsumi , Sugawara Satomi , Okamura Nobuyuki , Mugikura Shunji , Umetsu Atsushi , Murata Takanori , Nagasaka Tatsuo , Kudo Yukitsuka , Tashiro Manabu , Watanuki Shoichi , Nishizawa Masatoyo , Tokutake Takayoshi , Ishikawa Saeri , Kishida Emiko , Sato Nozomi , Hagiwara Mieko , Yamanaka Kumi , Watanabe Takeyuki , Takasugi Taeko , Inagawa Shoichi , Naito Kenichi , Awaji Masanori , Kanazawa Tsutomu , Okamoto Kouiti , Ikeda Masaki , Tasiro Yuiti , Nagamine Syunn , Kurose Sathiko , Yamazaki Tsuneo , Katsuyama Shiori , Fukushima Sayuri , Koya Etsuko , Amanuma Makoto , Ujita Kouiti , Kishi Kazuhiro , Tuda Kazuhisa , Oriuti Noboru , Mizukami Katsuyoshi , Arai Tetsuaki , Nakajima Etsuko , Miyamoto Katsumi , Kobayashi Tomoya , Itoya Saori , Ookubo Jun , Akatsu Toshiya , Anzai Yoshiko , Ikegaki Junya , Katou Yuuichi , Kimura Kaori , Saitou Hajime , Shinoda Kazuya , Someya Satoka , Taguchi Hiroko , Tashiro Kazuya , Tanaka Masaya , Nemoto Tatsuya , Wakabayashi Ryou , Watanabe Daisuke , Saotome Kousaku , Kuchii Ryou , Takano Harumasa , Suhara Tetsuya , Shinoto Hitoshi , Shimada Hitoshi , Higuchi Makoto , Mori Takaaki , Ito Hiroshi , Obata Takayuki , Fukushima Yoshiko , Suzuki Kazuko , Izumida Izumi , Tanimoto Katsuyuki , Shiraishi Takahiro , Shinotoh Hitoshi , Shiba Junko , Yano Hiroaki , Satake Miki , Nakui Aimi , Ebihara Yae , Hasegawa Tomomi , Yoshiyama Yasumasa , Kato Mami , Ogata Yuki , Fujikawa Hiroyuki , Araki Nobuo , Nakazato Yoshihiko , Sasaki Takahiro , Shimadu Tomokazu , Yoshimaru Kimiko , Imabayashi Etsuko , Yasuda Asako , Ozawa Keiko , Yamamoto Etuko , Nakamata Natsumi , Miyauchi Noriko , Hashimoto Rieko , Unezawa Taishi , Ichikawa Takafumi , Hayashi Hiroki , Yamagishi Masakazu , Mihara Tunemichi , Hirano Masaya , Watanabe Shinichi , Fukuhara Junichiro , Matsudo Hajime , Saito Nobuyuki , Iwata Atsushi , Kowa Hisatomo , Hayashi Toshihiro , Ihara Ryoko , Miyagawa Toji , Yoshida Mizuho , Koide Yuri , Samura Eriko , Fujii Kurumi , Watanabe Kaori , Orihara Nagae , Momose Toshimitsu , Takahashi Miwako , Arai Takuya , Kojima Yoshiki , Kunimatsu Akira , Mori Harushi , Goto Masami , Sarashina Takeo , Uzuki Syuichi , Katou Seiji , Sekine Yoshiharu , Takauchi Yukihiro , Kagami Chiine , Kanemaru Kazutomi , Nishina Yasushi , Sakaibara Maria , Okazaki Yumiko , Okada Rieko , Obata Maki , Takao Masaki , Iwata Yuko , Minami Mizuho , Hanabusa Yasuko , Shingyouji Hanae , Tottori Kyoko , Tokumaru Aya , Ichinose Makoto , Kume Kazuya , Kahashi Syunsuke , Arima Kunimasa , Tanaka Shin , Nagahusa Yuko , Sakata Masuhiro , Okazaki Mitsutoshi , Yamada Maki , Tukamoto Tadashi , Kodama Tiine , Takeuchi Tomoko , Ozawa Keiichiro , Kawaji Yoshiko , Tottori Kyouko , Nakata Yasuhiro , Sawada Satoshi , Mimatsu Makoto , Nakkamura Daisuke , Tamaru Takeshi , Horiuchi Shunichirou , Arai Heii , Ota Tsuneyoshi , Kodaka Aiko , Tagata Yuko , Nakada Tomoko , Iseki Eizo , Sato Kiyoshi , Fujishiro Hiroshige , Murayama Norio , Suzuki Masaru , Kimura Satoshi , Takahashi Masanobu , Hanyu Haruo , Sakurai Hirofumi , Umahara Takahiko , Kanetaka Hidekazu , Arashino Kaori , Murakami Mikako , Kito Ai , Miyagi Seiko , Doi Kaori , Sasaki Kazuyoshi , Yamazaki Mineo , Ishiwata Akiko , Arai Yasushi , Nogami Akane , Fukuda Sumiko , Kozaki Koichi , Yamada Yukiko , Kimura Sayaka , Machida Ayako , Kobayashi Kuninori , Mizusawa Hidehiro , Sanjo Nobuo , Watanabe Mutsufusa , Ohkubo Takuya , Utashiro Hiromi , Matsumoto Yukiko , Hagiya Kumiko , Miyama Yoshiko , Shibuya Hitoshi , Ohashi Isamu , Toriihara Akira , Shinozaki Takako , Hiraki Haruko , Ohtani Shinichi , Matsui Toshifumi , Toyama Tomomi , Sakurai Hideki , Sugiura Kumiko , Hayasaka Yu , Taguchi Hirofumi , Hatashita Shizuo , Imuta Akari , Matsudo Akiko , Wakebe Daichi , Hayakawa Hideki , Ono Mitsuhiro , Ohara Takayoshi , Washimi Yukihiko , Arahata Yutaka , Takeda Akinori , Yamaoka Akiko , Tsujimoto Masashi , Kawai Takiko , Honda Ai , Konagaya Yoko , Hattori Hideyuki , Yoshiyama Kenji , Miura Rina , Sakurai Takashi , Hisayuki Miura , Endou Hidetoshi , Satake Syousuke , Hong Young Jae , Iwai Katsunari , Suenaga Masaki , Morita Sumiko , Itou Kengo , Kato Takashi , Fujiwara Ken , Katou Rikio , Koyama Mariko , Fukaya Naohiko , Tsuji Akira , Shimizu Hitomi , Fujisawa Hiroyuki , Nakazawa Tomoko , Koyama Satoshi , Sakata Takanori , Yamada Masahito , Yoshita Mitsuhiro , Samuraki Miharu , Ono Kenjiro , Shinohara Moeko , Soshi Yuki , Niwa Kozue , Doumoto Chiaki , Hata Mariko , Matsushita Miyuki , Tsukiyama Mai , Takeda Nozomi , Yonezawa Sachiko , Matsunari Ichiro , Matsui Osamu , Ueda Fumiaki , Ryu Yasuji , Sakamoto Masanobu , Ouchi Yasuomi , Fujita Yumiko , Chita Madoka , Majima Rika , Tsubota Hiromi , Shirasawa Umeo , Sugimori Masashi , Ariya Wataru , Hagiwara Yuuzou , Tanizaki Yasuo , Fukuyama Hidenao , Tanaka-Urayama Shizuko , Urayama Shin-Ichi , Takahashi Ryosuke , Uemura Kengo , Takechi Hajime , Namiki Chihiro , Kihara Takeshi , Yamauchi Hiroshi , Maeda Emiko , Saito Natsu , Satomi Shiho , Kabata Konomi , Okada Tomohisa , Ishizu Koichi , Kawase Shigeto , Fukumoto Satoshi , Nakagawa Masanori , Kondo Masaki , Niwa Fumitoshi , Mizuno Toshiki , Oishi Yoko , Yamazaki Mariko , Yamaguchi Daisuke , Tokuda Takahiko , Ito Kyoko , Asano Yoku , Hamaguchi Chizuru , Yamada Kei , Okuyama Chio , Akazawa Kentaro , Matsushima Shigenori , Matsuo Takamasa , Nakagawa Toshiaki , Nii Takeshi , Nishida Takuji , Kiuchi Kuniaki , Fukusumi Masami , Watanabe Hideyuki , Taoka Toshiaki , Nogi Akihiro , Takeda Masatoshi , Tanaka Toshihisa , Kazui Hiroaki , Kudo Takashi , Okochi Masayasu , Morihara Takashi , Tagami Shinji , Takaya Masahiko , Wada Tamiki , Yokokoji Mikiko , Sugiyama Hiromichi , Yamamoto Daisuke , Nomura Keiko , Tomioka Mutsumi , Sato Naoyuki , Hayashi Noriyuki , Takeda Shuko , Uchida Eiichi , Ikeda Yoshiyuki , Murakami Mineto , Miki Takami , Shimada Hiroyuki , Ataka Suzuka , Takeda Akitoshi , Iwamoto Yuki , Kanemoto Motokatsu , Takeuchi Jun , Azuma Rie , Tagawa Naomi , Masao Junko , Matsumoto Yuka , Kikukawa Yuko , Fujii Hisako , Matsumura Junko , Shiomi Susumu , Kawabe Joji , Shimonishi Yoshihiro , Higashida Mitsuji , Sahara Tomohiro , Yamanaga Takashi , Miki Yukio , Sakamoto Shinichi , Tsushima Hiroyuki , Maeda Kiyoshi , Yamamoto Yasuji , Sakai Kazuo , Oda Haruhiko , Tahara Yoshihiko , Kawamata Toshio , Akisaki Taichi , Adachi Mizuho , Kuranaga Masako , Takegawa Sachi , Terada Seishi , Kishimoto Yuki , Takeda Naoya , Imai Nao , Yabe Mayumi , Wada Reiko , Ishihara Takeshi , Honda Hajime , Yokota Osamu , Ida Kentaro , Anami Daigo , Inoue Seiji , Matsushita Toshi , Hiramatsu Shinsuke , Tonbara Hiromi , Yamamoto Reiko , Nakashima Kenji , Wada-Isoe Kenji , Yamasaki Saori , Yamashita Eijiro , Nakamura Yu , Ishikawa Ichiro , Danjo Sonoko , Shinohara Tomomi , Kashimoto Yuka , Ueno Miyuki , Nishiyama Yoshihiro , Yamamoto Yuka , Kimura Narihide , Ogawa Kazuo , Sasakawa Yasuhiro , Ishimori Takashi , Maeda Yukito , Yamada Tatsuo , Ouma Shinji , Fukuhara-Kaneumi Aika , Sakamoto Nami , Nagao Rie , Yoshimitsu Kengo , Kuwabara Yasuo , Nakamuta Ryuji , Tanaka Minoru , Ikeda Manabu , Yatabe Yuusuke , Hashimoto Mamoru , Kaneda Keiichirou , Honda Kazuki , Ichimi Naoko , Morinaga Mariko , Noda Miyako , Akatuka Fumi , Kitajima Mika , Hirai Toshinori , Shiraishi Shinya , Amano Naoji , Washizuka Shinsuke , Hagiwara Tetsuya , Okada Yatsuka , Ogihara Tomomi , Takahashi Toru , Inuzuka Shin , Sugiyama Nobuhiro , Yasaki Takehiko , Kitayama Minori , Owa Tomonori , Ryokawa Akiko , Takeuchi Rie , Goto Satoe , Yamauchi Keiko , Ito Mie , Kaneko Tomoki , Ueda Hitoshi , Ikeda Shuichi , Mihara Ban , Kubo Hirofumi , Takano Akiko , Yasui Gou , Akuzawa Masami , Yamaguchi Kaori , Odawara Toshinari , Oota Naomi , Shimamura Megumi , Sugiyama Mikiko , Watanabe Atsushi , Takebayashi Shigeo , Hayakawa Yoshigazu , Idegawa Mitsuhiro , Toya Noriko , Ishii Kazunari 
Published: February 2024

Abstract
Background
Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.

Methods
In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.

Results
The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.

Conclusions
We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.