P. Adib-Samii, N. Rost, M. Traylor, W. Devan, A. Biffi, S. Lanfranconi, K. Fitzpatrick, S. Bevan, A. Kanakis, V. Valant, A. Gschwendtner, R. Malik, A. Richie, D. Gamble, H. Segal, E. A. Parati, E. Ciusani, E. G. Holliday, J. Maguire, J. Wardlaw, B. Worrall, J. Bis, K. L. Wiggins, W. Longstreth, S. J. Kittner, Y. C. Cheng, T. Mosley, G. J. Falcone, K. L. Furie, C. Leiva-Salinas, B. C. Lau, M. S. Khan, P. Sharma, M. Fornage, B. D. Mitchell, B. M. Psaty, C. Sudlow, C. Levi, G. B. Boncoraglio, P. M. Rothwell, J. Meschia, M. Dichgans, J. Rosand, H. S. Markus, Australian Stroke Genetics Collabo , Wellcome Trust Case-Control Consor , METASTROKE , Int Stroke Genetics Consortium



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Markus, HS Univ London, London SW17 0RE, England St Georges Univ London, Stroke & Dementia Res Ctr, London, England Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA Univ Munich, Inst Stroke & Dementia Res, Klinikum Univ Munchen, Munich, Germany Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA Univ Oxford, Nuffield Dept Neurosci, Stroke Prevent Res Unit, Oxford OX1 2JD, England Fdn IRCCS Ist Neurol Carlo Besta, Dept Cerebrovasc Dis, Milan, Italy Fdn IRCCS Ist Neurol Carlo Besta, Lab Clin Pathol & Med Genet, Milan, Italy Univ Newcastle, Ctr Clin Epidemiol & Biostat, Hunter Med Res Inst, Callaghan, NSW 2308, Australia Univ Newcastle, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia Univ Newcastle, Prior Res Ctr Translat Neurosci & Mental Hlth, Callaghan, NSW 2308, Australia Univ Newcastle, Fac Hlth, Sch Nursing & Midwifery, Callaghan, NSW 2308, Australia Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland Univ Virginia, Charlottesville, VA USA Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA Vet Affairs Med Ctr, Baltimore, MD USA Univ Mississippi, Med Ctr, Jackson, MS 39216 USA Brown Univ, Dept Neurol, Providence, RI 02912 USA Univ Virginia, Dept Radiol, Charlottesville, VA USA Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England Univ Texas Hlth Sci Ctr Houston, Houston, TX USA Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

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Background and Purpose-Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke.
Methods-We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke.
Results-Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke.
Conclusions-This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.