Journal
STROKE
Volume 51, Issue 7, Pages 2111-2121Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.119.027544
Keywords
brain; genome-wide association study; neuroimaging; risk factors; white matter
Categories
Funding
- National Institute of Neurological Disorders and Stroke, National Institutes of Health [R01AG059874, P41EB015922, R56AG058854, U54 EB020403, R01AG022381, U54EB020403, R01NS115845]
- Medical Research Council
- Age UK
- Scottish Funding Council
- Row Fogo Trust
- Welcome Trust
- Cross Council Lifelong Health and Wellbeing Initiative
- Leverhulme Trust
- National Institute for Health Research
- Biotechnology and Biological Sciences Research Council
- UK Medical Research Council
- Icelandic Heart Association
- Althingi
- Austrian Science Fund (FWF)
- Australian National Health and Medical Research Council
- Austrian National Bank
- Anniversary Fund
- European Commission FP6 STRP
- European Community's 5th Framework Program
- European Community's 7th Framework Program
- Netherlands Organization for Scientific Research
- Netherlands Consortium for Healthy Aging
- Russian Foundation for Basic Research
- Russian Federal Agency of Scientific Organizations
- Central Norway Regional Health Authority
- Norwegian University of Science and Technology
- Norwegian National Advisory Unit for functional magnetic resonance imaging (MRI)
- Leipzig Research Center for Civilization Diseases (LIFE)
- Bristol-Myers Squibb
- Netherlands Heart Foundation
- French National Research Agency (ANR)
- Foundation Leducq
- Joint Programme of Neurodegenerative Disease research
- Bordeaux University
- Institut Pasteur de Lille
- labex DISTALZ
- Centre National de Genotypage
- Deutsche Forschungsgesellschaft (DFG) [WI 3342/3-1]
- European Union
- European Regional Development Fund
- Free State of Saxony within LIFE-Leipzig Research Center for Civilization Diseases [100329290, 713-241202, 14505/2470, 14575/2470]
- Max Planck Society
- State of Saxony
- Brain Foundation
- National Health and Medical Research Council (NHMRC) of Australia
- NHMRC of Australia
- Parkinson's UK
- Medical Research Council -Dementias Platform UK
- National Institute on Aging, Bethesda, MD [P30 AG 010129]
- NATIONAL INSTITUTE ON AGING [ZIAAG007270] Funding Source: NIH RePORTER
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [MR/R024065/1, MR/N027558/1, G1001245, MR/M013111/1, G0700704, MR/L023784/2, G0701120] Funding Source: UKRI
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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), andPOLR2F(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.
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