Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wen Wei, Vilmundur Gudnason, Nicole D. Deuker, Lloyd T. Elliott, Edith Hofer, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert Smith, Stella S. Trompet, Dina VojinovicRui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampwar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jain, Brian G. Kral, John W. Kwok, Leonie Lampe, David C.M. Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuth, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Maragret J. Wright, Qiong Yang, Moris Zoe, Siggi Siggurdsson, Arno Villringer, Helena Schmidt, Asta L. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichigans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Lenore Launer, Thomas H. Mosley, Joanna M. Wardlaw, M. Afran Ikram, Hieab H.H. Adams, Reinhold Schmidt, Stephen M. Smith, Charles Decarli, Perminder S. Sachdev, Myriam Fornage, Stephanie Debbette, Sudha Seshadri, Paul A. Nyquist

Research output: Contribution to journalArticlepeer-review

Abstract

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jun 27 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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