Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes
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.
Authors
- Kosho Matsuura
- Y. Shirai
- Ho Namkoong
- Shigeki Nakagome (ORCID: https://orcid.org/0000-0001-9613-975X)
- Yuichiro Doki
- Yojiro Mitsumoto
- Yoshio Yamamoto (ORCID: https://orcid.org/0000-0002-6352-6013)
- Takafumi Ojima (ORCID: https://orcid.org/0000-0003-1197-0574)
- Yuriko N. Koyanagi (ORCID: https://orcid.org/0000-0002-5675-3429)
- Yumiko Kasugai (ORCID: https://orcid.org/0000-0003-4764-4455)
- Hidetoshi Eguchi (ORCID: https://orcid.org/0000-0002-2318-1129)
- Kazuo Suzuki (ORCID: https://orcid.org/0000-0002-7186-5592)
- Mamoru Uemura
- Kenichi Yamamoto
- Jun Takayama
- Yasuhiko Fujita
- Aoxing Liu
- Yuko Kitagawa
- Hisaaki Afuso
- Seiya Imoto
- Akinori Kanai
- Kyuto Sonehara
- Go Sato (ORCID: https://orcid.org/0009-0000-1251-8403)
- Yoshiya Oda
- Shiori Nakano
- Shuzo Kobayashi
- Awaisa Ghazal
- Takashi Kadowaki
- Aarno Palotie
- Koichi Matsuda
- Motoki Iwasaki
- Mark J. Daly
- Yutaka Suzuki
- Yoshito Takeda
- Norie Sawada
- Keitaro Matsuo
- Atsushi Kumanogoh
- Ryuji Koike
- Andrea Ganna
- Seishi Ogawa
- Gen Tamiya
- the Japan COVID-19 Task Force
- Koichi Fukunaga
- Makoto Ishii
- Yukinori Okada
- the Biobank Japan Project
- Takayuki Morisaki
- Shuhei Azekawa
- Tsuyoshi Hata
- James F. Wilson
- Giulio Genovese
- FinnGen
- Takanori Hasaegawa
- Akinori Kimura
- Toshimasa Yamauchi
- Masayuki Yamamoto
- Yoshifumi Uwamino
Institutions
- Kanazawa University (JP)
- Broad Institute (US)
- Osaka Gakuin University (JP)
- University of Helsinki (FI)
- Harvard University (US)
- Tokyo University of Science (JP)
- Tohoku University (JP)
- Keio University (JP)
- Trinity College Dublin (IE)
- Kyoto University (JP)
- Western General Hospital (GB)
- Massachusetts General Hospital (US)
- Tokyo Institute of Psychiatry (JP)
- Fukuoka Tokushukai Hospital (JP)
- University of Tokyo Hospital (JP)
- RIKEN Center for Advanced Intelligence Project (JP)
- Institute for Molecular Medicine Finland (FI)
- Aichi Cancer Center (JP)
- Tohoku Medical Megabank Organization (JP)
- Centre for Global Health Research (CA)
- RIKEN Center for Integrative Medical Sciences (JP)
- Shonan Kamakura General Hospital (JP)
- Toranomon Hospital (JP)
- Nagoya University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Medicine
- Published
- 2026-02-23
- DOI
- https://doi.org/10.1038/s41591-026-04213-z
- Citations
- 1
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 30.93