Peer-Reviewed Publication
Nat Med2026;32(3):894-905.March 1, 2026Journal Article
Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes.
Go Sato1,2,3,4, Yuji Yamamoto5,6, Kyuto Sonehara7,5,8, Ryunosuke Saiki9, Takafumi Ojima7,5,8,10,11,12, Masahiro Kanai13,14,15,16, Aoxing Liu13,14,15,17,18, Ryuya Edahiro5,8,6, Yuya Shirai5,8,6,19, Shinichi Namba7,5,8, Ho Namkoong20, Takanori Hasaegawa21, Yuriko N Koyanagi22, Yumiko Kasugai22, Taiki Yamaji23, Shiori Nakano23, Giulio Genovese14,18,24, Timo P Sipilä15, Awaisa Ghazal15, Hiromu Tanaka25, Shuhei Azekawa25, Yoshifumi Uwamino26, Kenichi Yamamoto5,19,27,28, Ken Suzuki5,29, Tsuyoshi Hata30, Mamoru Uemura30, Yoshito Takeda6, Akinori Kanai31, Shinichi Higashiue32, Shuzo Kobayashi32,33, Hisaaki Afuso32, Kosho Matsuura32, Yojiro Mitsumoto32, Yasuhiko Fujita32, , , , Yoshiya Oda34, Yutaka Suzuki31, Takayuki Morisaki35, Makoto Ishii36, Yuko Kitagawa37, Ryuji Koike38, Akinori Kimura39, Seiya Imoto40, Satoru Miyano21, Takanori Kanai41, Jun Takayama10,11,12, Motoki Iwasaki23,42, Norie Sawada42, Koichi Fukunaga25, Keitaro Matsuo22,43, Atsushi Kumanogoh6,44, Yuichiro Doki30, Hidetoshi Eguchi30, Shigeki Nakagome45,46, Gen Tamiya10,11,12, Andrea Ganna13,14,15,18, Aarno Palotie13,14,15,18, Mark J Daly13,14,15,17,18, James F Wilson47,48, Masayuki Yamamoto10,11, Koichi Matsuda49, Seishi Ogawa9,50, Toshimasa Yamauchi29, Takashi Kadowaki51, Yukinori Okada52,53,54,55,56
1Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. gsato@m.u-tokyo.ac.jp.
2Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
3Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. gsato@m.u-tokyo.ac.jp.
4Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
5Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
6Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, the University of Osaka, Suita, Japan.
7Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
8Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
9Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
10Graduate School of Medicine, Tohoku University, Sendai, Japan.
11Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
12Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan.
13Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
14Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
15Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
16Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
17Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
18Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
19Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
20Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
21M&D Data Science Center, Institute of Science Tokyo, Tokyo, Japan.
22Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
23Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
24Department of Genetics, Harvard Medical School, Boston, MA, USA.
25Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
26Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
27Department of Pediatrics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
28Laboratory of Children's health and Genetics, Division of Health Sciences, Graduate School of Medicine, the University of Osaka, Suita, Japan.
29Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
30Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
31Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan.
32Tokushukai Group, Tokyo, Japan.
33Department of Kidney Disease & Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.
34Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
35Division of Molecular Pathology, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
36Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
37Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
38Health Science Research and Development Center (HeRD), Institute of Science Tokyo Hospital, Tokyo, Japan.
39Institute of Research, Institute of Science Tokyo, Tokyo, Japan.
40Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
41Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
42Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
43Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
44Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
45School of Medicine, Trinity College Dublin, Dublin, Ireland.
46Institute for the Study of Ancient Civilizations and Cultural Resources, Kanazawa University, Kanazawa, Japan.
47Centre for Global Health Research, Usher Institute, the University of Edinburgh, Edinburgh, UK.
48Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
49Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
50Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
51Toranomon Hospital, Tokyo, Japan.
52Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. yuki-okada@m.u-tokyo.ac.jp.
53Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
54Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yuki-okada@m.u-tokyo.ac.jp.
55Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
56Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
Abstract
Our understanding of the biological role of the Y chromosome remains limited. Here, we systematically profile germline Y haplogroups and somatic loss of the Y chromosome (LOY) in 122,683 East Asian males from BioBank Japan and 181,472 European males from the UK Biobank. A phenome-wide scan uncovers male-specific genetic regulation of complex traits, including pleiotropic effects of the Japanese-sp…
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