Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

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

Research output: Contribution to journalArticle

Abstract

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses-pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Original languageEnglish (US)
Pages (from-to)2111-2121
Number of pages11
JournalStroke
DOIs
StateAccepted/In press - 2020

Keywords

  • brain
  • genome-wide association study
  • neuroimaging
  • risk factors
  • white matter

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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