Genes From a Translational Analysis Support a Multifactorial Nature of White Matter Hyperintensities
Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative. METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE. RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1). CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.
Source: Stroke
Authors: Lorna M. Lopez, W. David Hill, Sarah E. Harris, Maria Valdes Hernandez, Susana Munoz Maniega, Mark E. Bastin, Emma Bailey, Colin Smith, Martin McBride, John McClure, Delyth Graham, Anna Dominiczak, Qiong Yang, Myriam Fornage, M. Arfan Ikram, Stephanie Debette, Lenore Launer, Joshua C. Bis, Reinhold Schmidt, Sudha Seshadri, David J. Porteous, John Starr, Ian J. Deary, Joanna M. Wardlaw
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: School of Medicine, Boston University, Wellcome Trust, Cedars-Sinai Medical Center, British Neuropathological Society, Scottish Funding Council, European Commission, ZonMw, Hartstichting, Erasmus Medisch Centrum, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Medizinische Universität Graz, Hjartavernd, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1028935811, G1052397333, G1093531541, G1194337659, G1224608327, G1243299691, UC Davis Alzheimer's Disease Core Center, G1379949353, G1397335784, G1401438683, G1412333385, G1416583647, G1460387277, G1462415530, G1490530680, G1495020029, G1527150935, G1691174148, UCLA Clinical and Translational Science Institute, G1727292203, G1742450553, G1890355377, G1909643007, G2153629593, G2172647976, G2193588257, G2217057004, G230712557, G232440474, Genetic Markers of Brain Aging, G236442059, G2450915342, G250621538, G2555954497, G2663518188, G274585943, G277826483, G2786044735, G2791745117, G2800149121, G2818913090, G2847759872, G2861369480, G2882309788, G2918387404, G2989067737, G301743239, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, G3114902838, G3137375862, G3145043064, G3152385821, G3169706684, G3205625555, UCLA Clinical and Translational Science Institute, G3370719899, G3402222819, G3462919067, G3507024915, G3531780063, G3540777072, G3560915123, G36433118, G3667269547, G3667528909, G3692229207, G36937976, G3875685175, G3918109904, G4012114008, G412671775, G4167445418, G4200864717, G423252844, G4244732650, G445457422, G4524389906, G463297664, G4641403149, G4660668308, G4746977625, G4824283243, G4856618060, G4987078009, G500195777, G5067462658, G5125936451, G5167412771, G5281659474, G536099884, G5386252567, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5457026379, G5479317095, G5541294421, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G5558075022, G567847597, G573134505, CHARGE consortium: omics discovery for CVD and aging phenotypes, G61834786, G6195637971, G6296967160, G6361934619, MRI, Genetics & Cognitive Precursors of AD and Dementia, European large-scale functional genomics in the rat for translational research, G6552090923, G65980962, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, G6805325053, G6832344490, G687544517, G6902273418, G693548699, G7007046788, A genome-wide association study of non-pathological cognitive ageing, G7035200923, G7372779492, G7373387228, G7431531211, G7505613430, G764651519, G766700449, G766843672, G777822606, G8008854164, G80149192, G806768229, G8068269535, G8184890991, G8215766172, G8260701975, G8506930532, COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA, G859984287, Hormonal trajectories in aging, G8798930353, G8892155751, G8937114048, G9000018826, G9000027259, G9000030080, G9000050378, G9000065537, G9000069887, G9000109038, G9000111987, G9000124674, G9000140433, G9000143860, G9000145448, G9000155493, G9000159977, G9000194162, G9000239991, G9000294005, G9000354881, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, G905887895, G960597250
OpenAlex ID: W1982947392