{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:46:00Z","timestamp":1787755560477,"version":"build-2784847793"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,3,25]],"date-time":"2017-03-25T00:00:00Z","timestamp":1490400000000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT072952"],"award-info":[{"award-number":["WT072952"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000364","name":"Stroke Association","doi-asserted-by":"publisher","award":["TSA 2010\/01"],"award-info":[{"award-number":["TSA 2010\/01"]}],"id":[{"id":"10.13039\/501100000364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000364","name":"Stroke Association","doi-asserted-by":"publisher","award":["TSA 2013\/01"],"award-info":[{"award-number":["TSA 2013\/01"]}],"id":[{"id":"10.13039\/501100000364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"California Department of Fish and Game","doi-asserted-by":"publisher","award":["CRC 1123, B3"],"award-info":[{"award-number":["CRC 1123, B3"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC 250157"],"award-info":[{"award-number":["ERC 250157"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Genome\u2010wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger\u2010onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age\u2010at\u2010onset informed GWAS meta\u2010analysis, including a large younger\u2010onset SVS population, to identify novel associations with stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a three\u2010stage age\u2010at\u2010onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}]\u2009=\u20091.16 [1.10\u20131.22];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.2\u2009\u00d7\u200910\n                      <jats:sup>\u22129<\/jats:sup>\n                      ). The lead single\u2010nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI]\u2009=\u20091.10 [1.05\u20131.16];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20095.3\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ; N\u2009=\u20093,670), but not intracerebral hemorrhage (OR [95% CI]\u2009=\u20090.97 [0.84\u20131.12];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of\n                      <jats:italic>ZCCHC14<\/jats:italic>\n                      in arterial tissues (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20099.4\u2009\u00d7\u200910\n                      <jats:sup>\u22127<\/jats:sup>\n                      ) and DNA methylation at probe cg16596957 in whole blood (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20095.3\u2009\u00d7\u200910\n                      <jats:sup>\u22126<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      16q24.2 is associated with SVS. Associations of the locus with expression of\n                      <jats:italic>ZCCHC14<\/jats:italic>\n                      and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383\u2013394\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24840","type":"journal-article","created":{"date-parts":[[2016,12,20]],"date-time":"2016-12-20T11:02:44Z","timestamp":1482231764000},"page":"383-394","source":"Crossref","is-referenced-by-count":84,"title":["Genetic variation at 16q24.2 is associated with small vessel stroke"],"prefix":"10.1002","volume":"81","author":[{"given":"Matthew","family":"Traylor","sequence":"first","affiliation":[{"name":"Department of Medical and Molecular Genetics King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen Ludwig\u2010Maximilians University Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike A.","family":"Nalls","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Cotlarciuc","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL) London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Radmanesh","sequence":"additional","affiliation":[{"name":"Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital Boston MA"},{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology Massachusetts General Hospital Boston MA"},{"name":"Center for Human Genetic Research, Massachusetts General Hospital Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudmar","family":"Thorleifsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/AMGEN Reykjavik Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken B.","family":"Hanscombe","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Langefeld","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine Winston\u2010Salem NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danish","family":"Saleheen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia S.","family":"Rost","sequence":"additional","affiliation":[{"name":"J. Philip Kistler Stroke Research Center, Department of Neurology Massachusetts General Hospital Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idil","family":"Yet","sequence":"additional","affiliation":[{"name":"Department of Twin Research &amp; Genetic Epidemiology King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim D.","family":"Spector","sequence":"additional","affiliation":[{"name":"Department of Twin Research &amp; Genetic Epidemiology King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordana T.","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Twin Research &amp; Genetic Epidemiology King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eilis","family":"Hannon","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, University of Exeter Exeter United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Mill","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, University of Exeter Exeter United Kingdom"},{"name":"Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology and Neuroscience, King's College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Inserm Research Center for Epidemiology and Biostatistics (U897)\u2013Team Neuroepidemiology Bordeaux France"},{"name":"University of Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Debette","sequence":"additional","affiliation":[{"name":"Inserm Research Center for Epidemiology and Biostatistics (U897)\u2013Team Neuroepidemiology Bordeaux France"},{"name":"University of Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Bis","sequence":"additional","affiliation":[{"name":"Cardiovascular Health Research Unit, Department of Medicine University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"W.T.","family":"Longstreth","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Epidemiology University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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