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The aim of this study was to elucidate the contribution of hereditary CSVD\u2010related genes to CSVD\u2010related MRI findings in a general Japanese population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed datasets from 324 individuals aged \u2265\u200950\u2009years in Tohoku Medical Megabank (TMM), focusing on MRI markers and variants of\n                      <jats:italic>NOTCH3, ABCC6, COL4A1, COL4A2, GLA, HTRA1<\/jats:italic>\n                      , and\n                      <jats:italic>TREX1<\/jats:italic>\n                      genes. Background factors included age, sex, hypertension, diabetes, dyslipidemia, hyperuricemia, alcohol drinking, and smoking.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pathogenic variant carriers were identified within\n                      <jats:italic>ABCC6<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920), but not other genes. To compare with previous studies including rare\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      variants regardless of pathogenicity, we included 24 rare functional variants of\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      . We performed a gene\u2010based analysis using the burden test and sequence kernel association test (SKAT) adjusted for background factors, between WMH\/lacune and\n                      <jats:italic>ABCC6\/NOTCH3.<\/jats:italic>\n                      The only significant finding was the correlation between WMH volume and rare\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      variants by SKAT, both with the basic model, adjusted for age, sex, and hypertension (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.045), and full model, adjusted for all background factors (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.027). We also analyzed the association between intracranial major artery stenosis\/occlusion (ICASO) and\n                      <jats:italic>RNF213<\/jats:italic>\n                      p.Arg4810Lys, the East Asian\u2010specific variant susceptible to ICASO; however, we failed to identify a significant correlation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study suggests that\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      may contribute to WMH volume in a general Japanese population.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ggi.70400","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T10:57:24Z","timestamp":1770807444000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Significant Correlation Between White Matter Hyperintensity Volume and Rare\n                    <scp>\n                      <i>NOTCH3<\/i>\n                    <\/scp>\n                    Variants in the General Japanese Population"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-2507","authenticated-orcid":false,"given":"Ikuko","family":"Mizuta","sequence":"first","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumio","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Division of Ultrahigh 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