ArticleNature medicine2026
Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes.
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In one paragraph
Article in Nature medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2citing papers in PubMed
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Who cites it
2 citing papers in PubMed.
- Genetic basis of Asian diabetes.Journal of diabetes investigation · 2026Review
- Elucidating genetic backgrounds of myasthenia gravis in Japanese by genome-wide association studies and multi-omics analyses of thymoma.Nature communications · 2026Article
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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
67 authors.
Go Sato *Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. gsato@m.u-tokyo.ac.jp.ORCID http://orcid.org/0009-0000-1251-8403
Yuji Yamamoto *Department of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0002-5489-5079
Kyuto SoneharaDepartment of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0002-4536-1761
Ryunosuke SaikiDepartment of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.ORCID http://orcid.org/0000-0001-6984-7187
Takafumi OjimaDepartment of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Masahiro KanaiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5165-4408
Aoxing LiuAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9155-1494
Ryuya EdahiroDepartment of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0001-5009-6408
Yuya ShiraiDepartment of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0002-0518-9020
Shinichi NambaDepartment of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0002-7486-3146
Ho NamkoongDepartment of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
Takanori HasaegawaM&D Data Science Center, Institute of Science Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0001-7251-9950
Yuriko N KoyanagiDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.ORCID http://orcid.org/0000-0002-5675-3429
Yumiko KasugaiDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.ORCID http://orcid.org/0000-0003-4764-4455
Taiki YamajiDivision of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
Shiori NakanoDivision of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.ORCID http://orcid.org/0000-0001-5762-850X
Giulio GenoveseProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Timo P SipiläInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0001-6739-1606
Awaisa GhazalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Hiromu TanakaDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Shuhei AzekawaDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0001-5538-6324
Yoshifumi UwaminoDepartment of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
Kenichi YamamotoDepartment of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0001-9594-7050
Ken SuzukiDepartment of Statistical Genetics, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0003-1065-3593
Tsuyoshi HataDepartment of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
Mamoru UemuraDepartment of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
Yoshito TakedaDepartment of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, the University of Osaka, Suita, Japan.
Akinori KanaiDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan.ORCID http://orcid.org/0000-0003-1555-6768
Shinichi HigashiueTokushukai Group, Tokyo, Japan.
Shuzo KobayashiTokushukai Group, Tokyo, Japan.
Hisaaki AfusoTokushukai Group, Tokyo, Japan.
Kosho MatsuuraTokushukai Group, Tokyo, Japan.
Yojiro MitsumotoTokushukai Group, Tokyo, Japan.
Yasuhiko FujitaTokushukai Group, Tokyo, Japan.
FinnGen
Japan COVID-19 Task Force
Biobank Japan Project
Yoshiya OdaDepartment of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Yutaka SuzukiDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan.ORCID http://orcid.org/0000-0003-4852-1879
Takayuki MorisakiDivision of Molecular Pathology, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0002-3738-6627
Makoto IshiiDepartment of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.ORCID http://orcid.org/0000-0003-4396-1664
Yuko KitagawaDepartment of Surgery, Keio University School of Medicine, Tokyo, Japan.
Ryuji KoikeHealth Science Research and Development Center (HeRD), Institute of Science Tokyo Hospital, Tokyo, Japan.
Akinori KimuraInstitute of Research, Institute of Science Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0002-4933-2132
Seiya ImotoDivision of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
Satoru MiyanoM&D Data Science Center, Institute of Science Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0002-1753-6616
Takanori KanaiDivision of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0002-1466-4532
Jun TakayamaGraduate School of Medicine, Tohoku University, Sendai, Japan.
Motoki IwasakiDivision of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
Norie SawadaDivision of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.ORCID http://orcid.org/0000-0002-9936-1476
Koichi FukunagaDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Keitaro MatsuoDivision of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.ORCID http://orcid.org/0000-0003-1761-6314
Atsushi KumanogohDepartment of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, the University of Osaka, Suita, Japan.ORCID http://orcid.org/0000-0003-4749-7117
Yuichiro DokiDepartment of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
Hidetoshi EguchiDepartment of Gastroenterological Surgery, Graduate School of Medicine, the University of Osaka, Suita, Japan.
Shigeki NakagomeSchool of Medicine, Trinity College Dublin, Dublin, Ireland.ORCID http://orcid.org/0000-0001-9613-975X
Gen TamiyaGraduate School of Medicine, Tohoku University, Sendai, Japan.
Andrea GannaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8147-240X
Aarno PalotieAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2527-5874
Mark J DalyAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0949-8752
James F WilsonCentre for Global Health Research, Usher Institute, the University of Edinburgh, Edinburgh, UK.
Masayuki YamamotoGraduate School of Medicine, Tohoku University, Sendai, Japan.ORCID http://orcid.org/0000-0002-9073-9436
Koichi MatsudaLaboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0001-7292-2686
Seishi OgawaDepartment of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.ORCID http://orcid.org/0000-0002-7778-5374
Toshimasa YamauchiDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.ORCID http://orcid.org/0000-0003-4827-6404
Takashi KadowakiToranomon Hospital, Tokyo, Japan.
Yukinori OkadaDepartment of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. yuki-okada@m.u-tokyo.ac.jp.ORCID http://orcid.org/0000-0002-0311-8472
Funding
Japan Agency for Medical Research and Development (AMED) JP223fa627001Japan Agency for Medical Research and Development (AMED) JP223fa627002Japan Agency for Medical Research and Development (AMED) JP223fa627010Japan Agency for Medical Research and Development (AMED) JP223fa627011Japan Agency for Medical Research and Development (AMED) JP23ek0410113Japan Agency for Medical Research and Development (AMED) JP23kk0305022Japan Agency for Medical Research and Development (AMED) JP23km0405217Japan Agency for Medical Research and Development (AMED) JP23tm0524002Japan Agency for Medical Research and Development (AMED) JP23zf0127008Japan Agency for Medical Research and Development (AMED) JP24gm1810011Japan Agency for Medical Research and Development (AMED) JP24wm0625504MEXT | Japan Science and Technology Agency (JST) JPMJMS2021MEXT | Japan Science and Technology Agency (JST) JPMJMS2024MEXT | Japan Science and Technology Agency (JST) JPMJSP2138MEXT | Japan Society for the Promotion of Science (JSPS) 25H01057
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.
Indexed as
Chromosomes, Human, YDiabetes Mellitus, Type 2Asian PeopleFemaleGenetic Predisposition to DiseaseGenetic Risk ScoreGenome-Wide Association StudyHaplotypesHumansJapanMaleMultifactorial InheritancePolymorphism, Single NucleotideUK BiobankWhite People
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