• Nicola J Armstrong, Karen A Mather, Muralidharan Sargurupremraj, Maria J Knol, Rainer Malik, Claudia L Satizabal, Lisa R Yanek, Wei Wen, Vilmundur G Gudnason, Nicole D Dueker, Lloyd T Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A Logue, Michelle Luciano, Markus Scholz, Albert V Smith, Stella Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S Beiser, Henry Brodaty, Ian J Deary, Christine Fennema-Notestine, Piyush G Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R Jack, Mark Jenkinson, Jiyang Jiang, Brian G Kral, John B Kwok, Leonie Lampe, C M Liewald David D Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)., Pauline Maillard, Jonathan Marchini, Mark E Bastin, Bernard Mazoyer, Lukas Pirpamer, Rafael Romero José J The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.). Department of Neurol, Gennady V Roshchupkin, Peter R Schofield, Matthias L Schroeter, David J Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W Vernooij, Veronica A Witte, Margaret J Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K Haberg, Cornelia M van Duijn, J Wouter Jukema, Martin Dichgans, Ralph L Sacco, Clinton B Wright, William S Kremen, Lewis C Becker, Paul M Thompson, Thomas H Mosley, Joanna M Wardlaw, M Arfan Ikram, Hieab H H Adams, Sudha Seshadri, Perminder S Sachdev, Stephen M Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, and Paul A Nyquist.
• Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.).
• Stroke. 2020 Jul 1; 51 (7): 2111-2121.

Background And PurposePeriventricular 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.MethodsParticipants 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.ResultsIn 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.ConclusionsOur 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.

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