2026-02-25 東京大学,大阪大学,理化学研究所,虎の門病院,慶應義塾大学,東北大学,愛知県がんセンター,国立がん研究センター,徳洲会グループ
計 30 万人以上の男性を対象とした Y 染色体変異の網羅的解析
＜関連情報＞
Y染色体上の生殖細胞系列および体細胞系列の遺伝子調節が2型糖尿病に寄与する Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes
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,FinnGen,the Japan COVID-19 Task Force,the Biobank Japan Project,… Yukinori Okada
Nature Medicine Published:23 February 2026
DOI:https://doi.org/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.
