03799nas a2200637 4500008004100000022001400041245010600055210006900161260001300230300001000243490000700253520205800260653000902318653002202327653001202349653001002361653001402371653001302385653001102398653003402409653001102443653002602454653000902480653003602489653000902525653002102534653001702555653001702572653003502589653001702624100002002641700001602661700002102677700002902698700002702727700002002754700001702774700001702791700002002808700001802828700001902846700002102865700001602886700002002902700002002922700002302942700001902965700001902984700002203003700002003025700002303045700001603068700001803084700002303102856003603125 2015 eng d a1524-462800aGenes from a translational analysis support a multifactorial nature of white matter hyperintensities.0 aGenes from a translational analysis support a multifactorial nat c2015 Feb a341-70 v463 a
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.
10aAged10aAlzheimer Disease10aAnimals10aBrain10aCausality10aDementia10aFemale10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aPolymorphism, Single Nucleotide10aRats10aRats, Inbred SHR10aRats, Wistar10aRisk Factors10aTranslational Medical Research10aWhite Matter1 aLopez, Lorna, M1 aHill, David1 aHarris, Sarah, E1 aHernandez, Maria, Valdes1 aManiega, Susana, Munoz1 aBastin, Mark, E1 aBailey, Emma1 aSmith, Colin1 aMcBride, Martin1 aMcClure, John1 aGraham, Delyth1 aDominiczak, Anna1 aYang, Qiong1 aFornage, Myriam1 aIkram, Arfan, M1 aDebette, Stephanie1 aLauner, Lenore1 aBis, Joshua, C1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aPorteous, David, J1 aStarr, John1 aDeary, Ian, J1 aWardlaw, Joanna, M uhttps://chs-nhlbi.org/node/6818