Paul M. Thompson, Joshua C. Bis, Julian N. Trollor, Siggi Siggurdsson, Leonie Lampe, Piyush Gampawar, Myriam Fornage, Neda Jahanshad, Dina Vojinovic, Jiyang Jiang, Christophe Tzourio, Helena Schmidt, Shuo Li, Ian J. Deary, Lewis C. Becker, Karen A. Mather, Najaf Amin, Rui Xia, Bernard Mazoyer, Arno Villringer, Albert V. Smith, Henry Brodaty, Jeroen van der Grond, Vilmundur Gudnason, Rainer Malik, Christine Fennema-Notestine, Brian G. Kral, Asta Håberg, Clinton B. Wright, David C. Liewald, Sudha Seshadri, Claudia L. Satizabal, Bruce M. Psaty, Ralph L. Sacco, Reinhold Schmidt, Lisa R. Yanek, Mark Jenkinson, Qiong Yang, Jose R. Romero, Fidel Alfaro-Almagro, Philippe Amouyel, Margaret J. Wright, William T. Longstreth, Muralidharan Sargurupremraj, Mark E. Bastin, John B.J. Kwok, M. Arfan Ikram, David J. Stott, Nicole Dueker, Lukas Pirpamer, Perminder S. Sachdev, Stéphanie Debette, Edith Hofer, Ludovica Griffanti, Alexa S. Beiser, Nicola J. Armstrong, Stephen M. Smith, Lloyd T. Elliott, Wei Wen, J. Wouter Jukema, William S. Kremen, Markus Scholz, Anbupalam Thalamuthu, Peter R. Schofield, Clifford R. Jack, Stella Trompet, Gennady V. Roshchupkin, Matthias L. Schroeter, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Meike W. Vernooij, Maria J. Knol, Pauline Maillard, Charles DeCarli, Jonathan Marchini, Rebecca F. Gottesman, Paul A. Nyquist, Martin Dichgans, Zoe Morris, Cornelia M. van Duijn, David Ames, Veronica A. Witte, Hieab H.H. Adams, Mark A. Logue, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, and Clinical Genetics
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.