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Genes from a translational analysis support a multifactorial nature of white matter hyperintensities.
Friday,2015-08-28 11:59 America/Los_Angeles — zdrager
| Title | Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Lopez, LM, W Hill, D, Harris, SE, Hernandez, MValdes, Maniega, SMunoz, Bastin, ME, Bailey, E, Smith, C, McBride, M, McClure, J, Graham, D, Dominiczak, A, Yang, Q, Fornage, M, Ikram, AM, Debette, S, Launer, L, Bis, JC, Schmidt, R, Seshadri, S, Porteous, DJ, Starr, J, Deary, IJ, Wardlaw, JM |
| Journal | Stroke |
| Volume | 46 |
| Issue | 2 |
| Pagination | 341-7 |
| Date Published | 2015 Feb |
| ISSN | 1524-4628 |
| Keywords | Aged, Alzheimer Disease, Animals, Brain, Causality, Dementia, Female, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Polymorphism, Single Nucleotide, Rats, Rats, Inbred SHR, Rats, Wistar, Risk Factors, Translational Medical Research, White Matter |
| Abstract | <p><b>BACKGROUND AND PURPOSE: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1161/STROKEAHA.114.007649 |
| Alternate Journal | Stroke |
| PubMed ID | 25586835 |
| PubMed Central ID | PMC4306534 |
| Grant List | AG-023629 / AG / NIA NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States AG-15928 / AG / NIA NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States AG033193 / AG / NIA NIH HHS / United States AG08122 / AG / NIA NIH HHS / United States AG16495 / AG / NIA NIH HHS / United States BB/C514623/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom CZB/4/517 / / Chief Scientist Office / United Kingdom DK063491 / DK / NIDDK NIH HHS / United States G0700704 / / Medical Research Council / United Kingdom G0701120 / / Medical Research Council / United Kingdom G1001245 / / Medical Research Council / United Kingdom G1001401 / / Medical Research Council / United Kingdom HL080295 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL093029 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States MR/K026992/1 / / Medical Research Council / United Kingdom R01 AG033193 / AG / NIA NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States R01HL093029 / HL / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01 HL096917 / HL / NHLBI NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States UL1RR033176 / RR / NCRR NIH HHS / United States Z01 AG007270-08 / / Intramural NIH HHS / United States |