Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes

Go Sato^#^{1

2

3

4}, Yuji Yamamoto^#^{5

6}, Kyuto Sonehara^{7

5

8}, Ryunosuke Saiki⁹, Takafumi Ojima^{7

5

8

10

11

12}, Masahiro Kanai^{13

14

15

16}, Aoxing Liu^{13

14

15

17

18}, Ryuya Edahiro^{5

8

6}, Yuya Shirai^{5

8

6

19}, Shinichi Namba^{7

5

8}, Ho Namkoong²⁰, Takanori Hasaegawa²¹, Yuriko N Koyanagi²², Yumiko Kasugai²², Taiki Yamaji²³, Shiori Nakano²³, Giulio Genovese^{14

18

24}, Timo P Sipilä¹⁵, Awaisa Ghazal¹⁵, Hiromu Tanaka²⁵, Shuhei Azekawa²⁵, Yoshifumi Uwamino²⁶, Kenichi Yamamoto^{5

19

27

28}, Ken Suzuki^{5

29}, Tsuyoshi Hata³⁰, Mamoru Uemura³⁰, Yoshito Takeda⁶, Akinori Kanai³¹, Shinichi Higashiue³², Shuzo Kobayashi^{32

33}, Hisaaki Afuso³², Kosho Matsuura³², Yojiro Mitsumoto³², Yasuhiko Fujita³²; FinnGen; Japan COVID-19 Task Force; Biobank Japan Project; Yoshiya Oda³⁴, Yutaka Suzuki³¹, Takayuki Morisaki³⁵, Makoto Ishii³⁶, Yuko Kitagawa³⁷, Ryuji Koike³⁸, Akinori Kimura³⁹, Seiya Imoto⁴⁰, Satoru Miyano²¹, Takanori Kanai⁴¹, Jun Takayama^{10

11

12}, Motoki Iwasaki^{23

42}, Norie Sawada⁴², Koichi Fukunaga²⁵, Keitaro Matsuo^{22

43}, Atsushi Kumanogoh^{6

44}, Yuichiro Doki³⁰, Hidetoshi Eguchi³⁰, Shigeki Nakagome^{45

46}, Gen Tamiya^{10

11

12}, Andrea Ganna^{13

14

15

18}, Aarno Palotie^{13

14

15

18}, Mark J Daly^{13

14

15

17

18}, James F Wilson^{47

48}, Masayuki Yamamoto^{10

11}, Koichi Matsuda⁴⁹, Seishi Ogawa^{9

50}, Toshimasa Yamauchi²⁹, Takashi Kadowaki⁵¹, Yukinori Okada^{52

53

54

55

56}

Affiliations

¹ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. gsato@m.u-tokyo.ac.jp.
² Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
³ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. gsato@m.u-tokyo.ac.jp.
⁴ Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
⁵ Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
⁶ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, the University of Osaka, Suita, Japan.
⁷ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
⁸ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹ Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
¹⁰ Graduate School of Medicine, Tohoku University, Sendai, Japan.
¹¹ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
¹² Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan.
¹³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹⁶ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁹ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
²⁰ Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
²¹ M&D Data Science Center, Institute of Science Tokyo, Tokyo, Japan.
²² Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
²³ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
²⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²⁵ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
²⁶ Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
²⁷ Department of Pediatrics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
²⁸ Laboratory of Children's health and Genetics, Division of Health Sciences, Graduate School of Medicine, the University of Osaka, Suita, Japan.
²⁹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁰ Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
³¹ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan.
³² Tokushukai Group, Tokyo, Japan.
³³ Department of Kidney Disease & Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.
³⁴ Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁵ Division of Molecular Pathology, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
³⁶ Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁷ Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
³⁸ Health Science Research and Development Center (HeRD), Institute of Science Tokyo Hospital, Tokyo, Japan.
³⁹ Institute of Research, Institute of Science Tokyo, Tokyo, Japan.
⁴⁰ Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
⁴¹ Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
⁴² Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
⁴³ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴⁴ Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
⁴⁵ School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁴⁶ Institute for the Study of Ancient Civilizations and Cultural Resources, Kanazawa University, Kanazawa, Japan.
⁴⁷ Centre for Global Health Research, Usher Institute, the University of Edinburgh, Edinburgh, UK.
⁴⁸ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁴⁹ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
⁵⁰ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
⁵¹ Toranomon Hospital, Tokyo, Japan.
⁵² Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵³ Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁴ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁵ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁶ Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.

^# Contributed equally.

PMID: 41731096
DOI: 10.1038/s41591-026-04213-z

Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes

Go Sato et al. Nat Med. 2026.

. 2026 Feb 23.

doi: 10.1038/s41591-026-04213-z. Online ahead of print.

Authors

Affiliations

¹ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. gsato@m.u-tokyo.ac.jp.
² Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
³ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. gsato@m.u-tokyo.ac.jp.
⁴ Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan. gsato@m.u-tokyo.ac.jp.
⁵ Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
⁶ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, the University of Osaka, Suita, Japan.
⁷ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
⁸ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹ Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
¹⁰ Graduate School of Medicine, Tohoku University, Sendai, Japan.
¹¹ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
¹² Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan.
¹³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹⁶ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁹ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
²⁰ Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
²¹ M&D Data Science Center, Institute of Science Tokyo, Tokyo, Japan.
²² Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
²³ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
²⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²⁵ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
²⁶ Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
²⁷ Department of Pediatrics, Graduate School of Medicine, the University of Osaka, Suita, Japan.
²⁸ Laboratory of Children's health and Genetics, Division of Health Sciences, Graduate School of Medicine, the University of Osaka, Suita, Japan.
²⁹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁰ Department of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
³¹ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan.
³² Tokushukai Group, Tokyo, Japan.
³³ Department of Kidney Disease & Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.
³⁴ Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁵ Division of Molecular Pathology, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
³⁶ Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁷ Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
³⁸ Health Science Research and Development Center (HeRD), Institute of Science Tokyo Hospital, Tokyo, Japan.
³⁹ Institute of Research, Institute of Science Tokyo, Tokyo, Japan.
⁴⁰ Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
⁴¹ Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
⁴² Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
⁴³ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴⁴ Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan.
⁴⁵ School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁴⁶ Institute for the Study of Ancient Civilizations and Cultural Resources, Kanazawa University, Kanazawa, Japan.
⁴⁷ Centre for Global Health Research, Usher Institute, the University of Edinburgh, Edinburgh, UK.
⁴⁸ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁴⁹ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
⁵⁰ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
⁵¹ Toranomon Hospital, Tokyo, Japan.
⁵² Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵³ Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁴ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁵ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.
⁵⁶ Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), the University of Osaka, Suita, Japan. yuki-okada@m.u-tokyo.ac.jp.

^# Contributed equally.

PMID: 41731096
DOI: 10.1038/s41591-026-04213-z

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-specific haplogroup D on height and type 2 diabetes (T2D). LOY increases T2D risk in East Asians but is associated with reduced T2D risk in Europeans. In East Asians, LOY contributes to T2D incidence particularly among males with lower polygenic risk scores, providing a compensatory explanation for disease risk beyond germline genetics. Incorporating sex-chromosome variation improves polygenic prediction of T2D risk in both sexes. Single-cell analyses reveal cell type-specific accumulation of LOY across tissues and disease contexts, with LOY in pancreatic β cells potentially impairing glucose metabolism. Our study demonstrates the clinical relevance of Y chromosome variation for diabetes risk prediction and management.

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Conflict of interest statement

Competing interests: G.G. declares a patent application PCT/WO2019/079493, which has been filed on the mosaic chromosomal alterations detection method used in this work. A. Ganna is the founder of Real World Genetics. A.P. is a member of the Pfizer Genetics Scientific Advisory Panel. M.J.D. is a founder of Maze Therapeutics. All other authors declare no competing interests.

References

1. Jobling, M. A. & Tyler-Smith, C. Human Y-chromosome variation in the genome-sequencing era. Nat. Rev. Gene.t 18, 485–497 (2017). - DOI
1. Sun, L., Wang, Z., Lu, T., Manolio, T. A. & Paterson, A. D. eXclusionarY: 10 years later, where are the sex chromosomes in GWASs? Am. J. Hum. Genet. 110, 903–912 (2023). - PubMed - PMC - DOI
1. The Y Chromosome Consortium. A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res. 12, 339–348 (2002).
1. Sato, Y. et al. Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men. Andrology 3, 520–525 (2015). - PubMed - DOI
1. Timmers, P. R. H. J. & Wilson, J. F. Limited effect of Y chromosome variation on coronary artery disease and mortality in UK Biobank—brief report. Arterioscler. Thromb. Vasc. Biol. 42, 1198–1206 (2022). - PubMed - PMC - DOI

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Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes

Affiliations

Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources