| Title: | Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes |
| Journal: | Nature Medicine |
| Published: | 23 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41731096/ |
| DOI: | https://doi.org/10.1038/s41591-026-04213-z |
Publication 17655
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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.</p>
18 Keywords
- Aged
- Asian People
- Chromosomes, Human, Y
- Diabetes Mellitus, Type 2
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Germ Cells
- Germ-Line Mutation
- Haplotypes
- Humans
- Insulin-Secreting Cells
- Japan
- Male
- Middle Aged
- Multifactorial Inheritance
- Polymorphism, Single Nucleotide
- White People
64 Authors
- Go Sato
- Yuji Yamamoto
- Kyuto Sonehara
- Ryunosuke Saiki
- Takafumi Ojima
- Masahiro Kanai
- Aoxing Liu
- Ryuya Edahiro
- Yuya Shirai
- Shinichi Namba
- Ho Namkoong
- Takanori Hasaegawa
- Yuriko N. Koyanagi
- Yumiko Kasugai
- Taiki Yamaji
- Shiori Nakano
- Giulio Genovese
- Timo P. Sipilä
- Awaisa Ghazal
- Hiromu Tanaka
- Shuhei Azekawa
- Yoshifumi Uwamino
- Kenichi Yamamoto
- Ken Suzuki
- Tsuyoshi Hata
- Mamoru Uemura
- Yoshito Takeda
- Akinori Kanai
- Shinichi Higashiue
- Shuzo Kobayashi
- Hisaaki Afuso
- Kosho Matsuura
- Yojiro Mitsumoto
- Yasuhiko Fujita
- Yoshiya Oda
- Yutaka Suzuki
- Takayuki Morisaki
- Makoto Ishii
- Yuko Kitagawa
- Ryuji Koike
- Akinori Kimura
- Seiya Imoto
- Satoru Miyano
- Takanori Kanai
- Jun Takayama
- Motoki Iwasaki
- Norie Sawada
- Koichi Fukunaga
- Keitaro Matsuo
- Atsushi Kumanogoh
- Yuichiro Doki
- Hidetoshi Eguchi
- Shigeki Nakagome
- Gen Tamiya
- Andrea Ganna
- Aarno Palotie
- Mark J. Daly
- James F. Wilson
- Masayuki Yamamoto
- Koichi Matsuda
- Seishi Ogawa
- Toshimasa Yamauchi
- Takashi Kadowaki
- Yukinori Okada
1 Application
| Application ID | Title |
|---|---|
| 47821 | Trans-ethnic GWAS meta-analysis and exploration of trait-relevant genetic architecture. |
Enabling scientific discoveries that improve human health