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

Nicola J. Armstrong(Murdoch University), Karen A. Mather(UNSW Sydney), Muralidharan Sargurupremraj(Université de Bordeaux), Maria J. Knol(Erasmus MC), Rainer Malik(Ludwig-Maximilians-Universität München), Claudia L. Satizábal(Boston University), Lisa R. Yanek(Johns Hopkins University), Wen Wei(UNSW Sydney), Vilmundur Guðnason(University of Iceland), Nicole D Deuker(University of Miami), Lloyd T. Elliott(Simon Fraser University), Edith Hofer(Medical University of Graz), Neda Jahanshad(University of Southern California), Shuo Li(Boston University), Mark Logue(Boston University), Michelle Luciano(University of Edinburgh), Markus Scholz(Leipzig University), Albert V. Smith(University of Iceland), Stella Trompet(Leiden University Medical Center), Dina Vojinović(Erasmus MC), Rui Xia(Brown Foundation), Fidel Alfaro‐Almagro(University of Oxford), David Ames(The University of Melbourne), Najaf Amin(Erasmus MC), Philippe Amouyel(Inserm), Alexa Beiser(Boston University), Henry Brodaty(UNSW Sydney), Ian J. Deary(University of Edinburgh), Christine Fennema‐Notestine(University of California San Diego), Piyush G Gampwar(Medical University of Graz), Rebecca F. Gottesman(Johns Hopkins University), Ludovica Griffanti(University of Oxford), Clifford R. Jack(Mayo Clinic in Arizona), Mark Jenkinson(University of Oxford), Jiyang Jain(UNSW Sydney), Brian G. Kral(Johns Hopkins University), John B. Kwok(The University of Sydney), Leonie Lampe(Max Planck Institute for Human Cognitive and Brain Sciences), David C. Liewald(University of Edinburgh), Pauline Maillard(University of California, Davis), Jonathan Marchini(Regeneron (United States)), Mark E. Bastin(University of Edinburgh), Bernard Mazoyer(Université de Bordeaux), Lukas Pirpamer(Medical University of Graz), José R. Romero(Boston University), Gennady V. Roshchupkin(Erasmus MC), Peter R. Schofield(UNSW Sydney), Matthias L. Schroeter(University Hospital Leipzig), David J. Stott(University of Glasgow), Anbupalam Thalamuth(UNSW Sydney), Julian N. Trollor(UNSW Sydney), Christophe Tzourio(Université de Bordeaux), Jeroen van der Grond(Leiden University Medical Center), Meike W. Vernooij(Erasmus MC), A. Veronica Witte(Max Planck Institute for Human Cognitive and Brain Sciences), Maragret J Wright(The University of Queensland), Qiong Yang(Boston University), Moris Zoe(The University of Queensland), Siggi Siggurdsson(Icelandic Heart Association), Arno Villringer(University Hospital Leipzig), Helena Schmidt(Medical University of Graz), Asta Håberg(Norwegian University of Science and Technology), Cornelia M. van Duijn(Erasmus MC), J. Wouter Jukema(Leiden University Medical Center), Martin Dichigans(German Center for Neurodegenerative Diseases), Ralph L. Sacco(University of Miami), Clinton B. Wright(National Institutes of Health), William S. Kremen(University of California San Diego), Lewis C. Becker(Johns Hopkins University), Paul M. Thompson(University of Southern California), Lenore J. Launer(National Institutes of Health), Thomas H. Mosley(University of Mississippi Medical Center), Joanna M. Wardlaw(University of Edinburgh), Mohammad Ikram(Erasmus MC), Hieab H.H. Adams(Erasmus MC), Reinhold Schmidt(Medical University of Graz), Stephen M. Smith(University of Oxford), Charles DeCarli, Perminder S. Sachdev(UNSW Sydney), Myriam Fornage(Brown Foundation), Stephanie Debbette(Université de Bordeaux), Sudha Seshadri(Boston University), Paul Nyquist(National Institutes of Health)
bioRxiv (Cold Spring Harbor Laboratory)
June 27, 2019
10.1101/683367
Cited by 1Open Access
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Abstract

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.

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