{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:06:21Z","timestamp":1779375981266,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,18]]},"group-title":"Genetics","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Hypertension is a highly heritable cardiovascular disorder and a major determinant of cardiometabolic disease, including diabetes. However, the regulatory genes and tissue-specific mechanisms underlying blood pressure variations remain incompletely understood.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Leveraging a well-characterized prospective population-based cohort comprised of 27,308 participants from the Singapore Chinese Health Study (SCHS), we evaluated genome-wide genetic associations for five blood pressure traits: hypertension status, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and pulse pressure (PP). Additionally, we conducted a transcriptome-wide association study (TWAS), integrating gene expression data from 49 tissues, followed by colocalization and fine-mapping to prioritize regulatory genes. Association of identified variants with incident diabetes was additionally evaluated in the longitudinal data.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We validated 10 blood pressure loci (\n                    <jats:italic>P<\/jats:italic>\n                    between 1.64 x 10\n                    <jats:sup>-20<\/jats:sup>\n                    \u2013 4.10 x 10\n                    <jats:sup>-8<\/jats:sup>\n                    ) and identified an East-Asian specific splice donor variant at the\n                    <jats:italic>COL21A1<\/jats:italic>\n                    gene associated with PP (rs149344559,\n                    <jats:italic>P<\/jats:italic>\n                    = 6.78 \u00d7 10\n                    <jats:sup>-10<\/jats:sup>\n                    ). Integrative analyses prioritized\n                    <jats:italic>FGF5<\/jats:italic>\n                    in kidney cortex and\n                    <jats:italic>ENPEP<\/jats:italic>\n                    in pituitary tissue as candidate regulatory genes. The blood pressure-lowering allele at\n                    <jats:italic>ENPEP<\/jats:italic>\n                    (T allele, rs1879056) was associated with reduced risk of incident diabetes. Mediation analysis demonstrated that approximately 21% of the genetic association with diabetes was mediated through MAP (P\n                    <jats:sub>indirect-effect<\/jats:sub>\n                    = 2 x 10\n                    <jats:sup>-16<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    This study refines genetic predispositions for blood pressure among East-Asians. We further delineate tissue-specific regulatory pathways underlying blood pressure variations and identify\n                    <jats:italic>ENPEP<\/jats:italic>\n                    -mediated dysfunctions linking blood pressure genetics to diabetes risk, underscoring integrated disease mechanisms.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.14.725285","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:25:37Z","timestamp":1779150337000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative Genomic Analyses Identify\n                  <i>COL21A1<\/i>\n                  and\n                  <i>ENPEP-FGF5<\/i>\n                  Regulatory Pathways for Blood Pressure Variation in East Asians"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6725-306X","authenticated-orcid":false,"given":"Zhi Chng","family":"Lau","sequence":"first","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"},{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"},{"name":"Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuling","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"Khoo Teck Puat \u2013 National University Children\u2019s Medical Institute, National University Health System, Singapore, Singapore"},{"name":"Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kar Seng","family":"Sim","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arshia","family":"Naaz","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umamaheswari","family":"Muniasamy","sequence":"additional","affiliation":[{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiea Chuen","family":"Khor","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"},{"name":"Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5674-6341","authenticated-orcid":false,"given":"Woon-Puay","family":"Koh","sequence":"additional","affiliation":[{"name":"Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"},{"name":"A*STAR Institute for Human Development and Potential (A*STAR IHDP), 30 Medical Drive, Brenner Centre for Molecular Medicine, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitaly A.","family":"Sorokin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"},{"name":"Department of Cardiac, Thoracic and Vascular Surgery, National University Hospital, National University Health System, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6608-2051","authenticated-orcid":false,"given":"Rajkumar","family":"Dorajoo","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore"},{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052107251082000_2026.05.14.725285v1.1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26010123"},{"key":"2026052107251082000_2026.05.14.725285v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)11911-8"},{"key":"2026052107251082000_2026.05.14.725285v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature10405"},{"key":"2026052107251082000_2026.05.14.725285v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.834"},{"key":"2026052107251082000_2026.05.14.725285v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0205-x"},{"key":"2026052107251082000_2026.05.14.725285v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001527"},{"key":"2026052107251082000_2026.05.14.725285v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0385-z"},{"key":"2026052107251082000_2026.05.14.725285v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3506"},{"key":"2026052107251082000_2026.05.14.725285v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02056-7"},{"key":"2026052107251082000_2026.05.14.725285v1.10","doi-asserted-by":"publisher","DOI":"10.1207\/S15327914nc392_5"},{"key":"2026052107251082000_2026.05.14.725285v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08675-8"},{"key":"2026052107251082000_2026.05.14.725285v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-018-1879-7"},{"key":"2026052107251082000_2026.05.14.725285v1.13","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-2350"},{"key":"2026052107251082000_2026.05.14.725285v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz070"},{"key":"2026052107251082000_2026.05.14.725285v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106546"},{"key":"2026052107251082000_2026.05.14.725285v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01274-x"},{"key":"2026052107251082000_2026.05.14.725285v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"2026052107251082000_2026.05.14.725285v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0184-y"},{"key":"2026052107251082000_2026.05.14.725285v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"2026052107251082000_2026.05.14.725285v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1229"},{"key":"2026052107251082000_2026.05.14.725285v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1133"},{"key":"2026052107251082000_2026.05.14.725285v1.22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa840"},{"key":"2026052107251082000_2026.05.14.725285v1.23","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.3727189"},{"key":"2026052107251082000_2026.05.14.725285v1.24","doi-asserted-by":"publisher","DOI":"10.1089\/bio.2015.0032"},{"key":"2026052107251082000_2026.05.14.725285v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.09.010"},{"key":"2026052107251082000_2026.05.14.725285v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06302-1"},{"key":"2026052107251082000_2026.05.14.725285v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004383"},{"key":"2026052107251082000_2026.05.14.725285v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0367-1"},{"key":"2026052107251082000_2026.05.14.725285v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyu176"},{"key":"2026052107251082000_2026.05.14.725285v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00931-x"},{"key":"2026052107251082000_2026.05.14.725285v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-04168-0"},{"key":"2026052107251082000_2026.05.14.725285v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07345-0"},{"key":"2026052107251082000_2026.05.14.725285v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j"},{"key":"2026052107251082000_2026.05.14.725285v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3405"},{"key":"2026052107251082000_2026.05.14.725285v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3654"},{"key":"2026052107251082000_2026.05.14.725285v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00713-x"},{"key":"2026052107251082000_2026.05.14.725285v1.37","doi-asserted-by":"crossref","unstructured":"D. Tuckwell , \u201cIdentification and analysis of collagen 1 XXI, a novel member of the FACIT collagen family,\u201d 2002. [Online]. Available: www.sanger.ac.ukrsoftwarerpfamr","DOI":"10.1016\/S0945-053X(01)00176-7"},{"key":"2026052107251082000_2026.05.14.725285v1.38","doi-asserted-by":"publisher","DOI":"10.2174\/1874192401610010048"},{"key":"2026052107251082000_2026.05.14.725285v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2017.11.043"},{"key":"2026052107251082000_2026.05.14.725285v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2022.04.045"},{"key":"2026052107251082000_2026.05.14.725285v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00909-9"},{"key":"2026052107251082000_2026.05.14.725285v1.42","doi-asserted-by":"publisher","DOI":"10.4172\/2153-0602.1000211"},{"key":"2026052107251082000_2026.05.14.725285v1.43","doi-asserted-by":"crossref","unstructured":"E. Vila-Porcile and P. Corvol , \u201cAngiotensinogen, Prorenin, and Renin Are Co-localized in the Secretory Granules of All Glandular Cells of the Rat Anterior Pituitary: An Immunoultrastructural Study,\u201d 1998. [Online]. Available: http:\/\/www.jhc.org","DOI":"10.1177\/002215549804600303"},{"key":"2026052107251082000_2026.05.14.725285v1.44","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-007-9065-7"},{"key":"2026052107251082000_2026.05.14.725285v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2017.12.005"},{"key":"2026052107251082000_2026.05.14.725285v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2018.01.010"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.14.725285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T14:25:20Z","timestamp":1779373520000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.14.725285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":46,"URL":"https:\/\/doi.org\/10.64898\/2026.05.14.725285","relation":{},"subject":[],"published":{"date-parts":[[2026,5,18]]},"subtype":"preprint"}}