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BACKGROUND AND PURPOSE:White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS:Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. RESULTS:A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. CONCLUSIONS:Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Original publication

DOI

10.1161/STROKEAHA.115.009252

Type

Journal article

Journal

Stroke

Publication Date

11/2015

Volume

46

Pages

3048 - 3057

Addresses

From the Department of Neurology (E.H., M.C., H.S., R.S.) and Institute for Medical Informatics, Statistics and Documentation (E.H.), Medical University of Graz, Graz, Austria; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.), Radiology (D.K.S.), and Neurology and Epidemiology (W.T.L.), University of Washington, Seattle; Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento (C.D.C., O.M.); Brown Foundation Institute of Molecular Medicine (M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center, Houston; Icelandic Heart Association, Kopavogur, Iceland (S.S., V.G., A.S.); Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia (V.S., M.C., C.M., T.P., R.B.); Departments of Cardiology (S.T., J.W.J.), Gerontology and Geriatrics (S.T., A.J.M.C., R.G.J.W.), Molecular Epidemiology (P.E.S.), and Radiology (M.B.), Leiden University Medical Center, Leiden, The Netherlands; Departments of Epidemiology (B.F.J.V., H.H.H.A., C.M.D., A.H., M.W.V., M.A.I.), Radiology (B.F.J.V., H.H.H.A., M.W.V., M.A.I.), and Medical Informatics (W.J.N.), Erasmus Medical Center, Rotterdam, The Netherlands; INSERM U897 (C.W., G.C., C.D., S.S., S.D.), CNRS-CEA UMR5296 (B.M.), and INSERM U708 (C.T.), Université Bordeaux Segalen, Bordeaux, France; Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany (C.W.); Department of Biostatistics, Boston University School of Public Health, MA (Q.Y., A.B., J.W.); INSERM U744, Pasteur Institute, Lille, France (P.A.); Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland (B.M.B.); INSERM U1161 and Lariboisière Hospital, Paris 7 University, Paris, France (G.C., S.S., S.D.); Centre for Medical Systems Biology, Leiden, The Netherlands (C.M.D.); Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom (I.F

Keywords

Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Humans, Disease Progression, Genetic Predisposition to Disease, Cohort Studies, Prospective Studies, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Leukoencephalopathies, White Matter