Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Armstrong N., Mather K., Sargurupremraj M., Knol M., Malik R., Satizabal C., Yanek L., Wei W., Gudnason V., Deuker N., Elliott L., Hofer E., Jahanshad N., Li S., Logue M., Luciano M., Scholz M., Smith A., Trompet S., Vojinovic D., Xia R., Alfaro-Almagro F., Ames D., Amin N., Amouyel P., Beiser A., Brodaty H., Deary I., Fennema-Notestine C., Gampwar P., Gottesman R., Griffanti L., Jack C., Jenkinson M., Jain J., Kral B., Kwok J., Lampe L., Liewald DCM., Maillard P., Marchini J., Bastin M., Mazoyer B., Pirpamer L., Romero JR., Roshchupkin G., Schofield P., Schroeter M., Stott D., Thalamuth A., Trollor J., Tzourio C., van der Grond J., Vernooij M., Witte V., Wright M., Yang Q., Zoe M., Siggurdsson S., Villringer A., Schmidt H., Haberg A., Van Duijn C., Jukema W., Dichigans M., Sacco R., Wright C., Kremen W., Becker L., Thompson P., Launer L., Mosley T., Wardlaw J., Ikram A., Adams HHH., Schmidt R., Smith S., Decarli C., Sachdev P., Fornage M., Debbette S., Seshadri S., Nyquist P.
We 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.