Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Armstrong NJ., Mather KA., Sargurupremraj M., Knol MJ., Malik R., Satizabal CL., Yanek LR., Wei W., Gudnason V., Deuker ND., Elliott LT., Hofer E., Jahanshad N., Li S., Logue MA., Luciano M., Scholz M., Smith A., Trompet SS., Vojinovic D., Xia R., Alfaro-Almagro F., Ames D., Amin N., Amouyel P., Beiser AS., Brodaty H., Deary IJ., Fennema-Notestine C., Gampwar PG., Gottesman R., Griffanti L., Jack CR., Jenkinson M., Jain J., Kral BG., Kwok JW., Lampe L., Liewald DCM., Maillard P., Marchini J., Bastin ME., Mazoyer B., Pirpamer L., Romero JR., Roshchupkin GV., Schofield PR., Schroeter ML., Stott DJ., Thalamuth A., Trollor J., Tzourio C., van der Grond J., Vernooij MW., Witte VA., Wright MJ., Yang Q., Zoe M., Siggurdsson S., Villringer A., Schmidt H., Haberg AL., Van Duijn CM., Jukema JW., Dichigans M., Sacco RL., Wright CB., Kremen WS., Becker LC., Thompson PM., Launer L., Mosley TH., Wardlaw JM., Ikram MA., Adams HHH., Schmidt R., Smith SM., Decarli C., Sachdev PS., Fornage M., Debbette S., Seshadri S., Nyquist PA.
AbstractWe conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.