| Title: |
Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes |
| Authors: |
FinnGen; the Japan COVID-19 Task Force; The Biobank Japan Project; Sato, Go; Yamamoto, Yuji; Sonehara, Kyuto; Saiki, Ryunosuke; Ojima, Takafumi; Kanai, Masahiro; Liu, Aoxing; Edahiro, Ryuya; Shirai, Yuya; Namba, Shinichi; Namkoong, Ho; Hasaegawa, Takanori; Koyanagi, Yuriko N.; Kasugai, Yumiko; Yamaji, Taiki; Nakano, Shiori; Genovese, Giulio; Sipilä, Timo P.; Ghazal, Awaisa; Tanaka, Hiromu; Azekawa, Shuhei; Uwamino, Yoshifumi; Yamamoto, Kenichi; Suzuki, Ken; Hata, Tsuyoshi; Uemura, Mamoru; Takeda, Yoshito; Kanai, Akinori; Higashiue, Shinichi; Kobayashi, Shuzo; Afuso, Hisaaki; Matsuura, Kosho; Mitsumoto, Yojiro; Fujita, Yasuhiko; Oda, Yoshiya; Suzuki, Yutaka; Morisaki, Takayuki; Ishii, Makoto; Kitagawa, Yuko; Koike, Ryuji; Kimura, Akinori; Imoto, Seiya; Miyano, Satoru; Kanai, Takanori; Takayama, Jun; Iwasaki, Motoki; Sawada, Norie; Ganna, Andrea; Palotie, Aarno; Daly, Mark J.; Okada, Yukinori |
| Contributors: |
Data Science Genetic Epidemiology Lab; Institute for Molecular Medicine Finland; Helsinki Institute of Life Science HiLIFE; Genomics of Neurological and Neuropsychiatric Disorders; Helsinki Institute of Life Science HiLIFE, Joint Activities; HUS Group; Research Programs Unit; Aarno Palotie / Principal Investigator |
| Publisher Information: |
Nature Research |
| Publication Year: |
2026 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Genetics; developmental biology; physiology; Mosaic loss; Design; Expression; Project; Blood |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We sincerely thank all the participants and investigators involved in this study, including BBJ, TMM and the Asian Immune Diversity Atlas. The HERPACC Study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Priority Areas of Cancer (17015018), Innovative Areas (221S0001) and the Japan Society for the Promotion of Science (JSPS) KAKENHI (no. 16H06277 and 22H04923 (CoBiA)), the Aichi Cancer Center Joint Research Project on Priority Areas and Cancer BioBank Aichi. The JPHC Study was supported by the National Cancer Center Research and Development Fund (23-A-31 (toku), 26-A-2, 29-A-4, 2020-J-4 and 2023-J-4 from 2011), and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie, AstraZeneca UK, Biogen MA, Bristol Myers Squibb (and Celgene Corporation & Celgene International II), Genentech, Merck Sharp & Dohme, Pfizer, GlaxoSmithKline Intellectual Property Development, Sanofi US Services, Maze Therapeutics, Janssen Biotech, Novartis and Boehringer Ingelheim International. The following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. We used data acquired from the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202) Database, a Human Islet Research Network (RRID:SCR_014393) consortium (UC4-DK-112217, U01-DK-123594, UC4-DK-112232, and U01-DK-123716). Y.Okada was supported by JSPS KAKENHI (25H01057) and AMED (JP23km0405217, JP23ek0109594, JP23ek0410113, JP23kk0305022, JP223fa627001, JP223fa627002, JP223fa627010, JP223fa627011, JP23zf0127008, JP23tm0524002, JP24wm0625504 and JP24gm1810011), JST Moonshot R&D (JPMJMS2021 and JPMJMS2024), Takeda Science Foundation, Ono Pharmaceutical Foundation for Oncology, Immunology, and Neurology, Bioinformatics Initiative of Graduate School of Medicine, the University of Osaka, Institute for Open and Transdisciplinary Research Initiatives, Center for Infectious Disease Education and Research, the Center for Advanced Modality and DDS, the University of Osaka and RIKEN TRIP initiative (AGIS). G.S. was supported by AMED (JP25kk0305029). Y.Y. was supported by JST SPRING (JPMJSP2138). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.; https://hdl.handle.net/10138/629850; 105031934505; 001697266200001 |
| Availability: |
https://hdl.handle.net/10138/629850 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.C81DF7A7 |
| Database: |
BASE |