Cerebral small vessel disease genomics and its implications across the lifespan

Sargurupremraj, M.; Suzuki, H.; Jian, X.Q.; Sarnowski, C.; Evans, T.E.; Bis, J.C.; ... ; Int Headache Genomics Consortium I (2020)

Article / Letter to editor

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

• All authors: Sargurupremraj, M.; Suzuki, H.; Jian, X.Q.; Sarnowski, C.; Evans, T.E.; Bis, J.C.; Eiriksdottir, G.; Sakaue, S.; Terzikhan, N.; Habes, M.; Zhao, W.; Armstrong, N.J.; Hofer, E.; Yanek, L.R.; Hagenaars, S.P.; Kumar, R.B.; Akker, E.B. van den; McWhirter, R.E.; Trompet, S.; Mishra, A.; Saba, Y.; Satizabal, C.L.; Beaudet, G.; Petit, L.; Tsuchida, A.; Zago, L.; Schilling, S.; Sigurdsson, S.; Gottesman, R.F.; Lewis, C.E.; Aggarwal, N.T.; Lopez, O.L.; Smith, J.A.; Hernandez, M.C.V.; Grond, J. van der; Wright, M.J.; Knol, M.J.; Dorr, M.; Thomson, R.J.; Bordes, C.; Grand, Q. le; Duperron, M.G.; Smith, A.V.; Knopman, D.S.; Schreiner, P.J.; Evans, D.A.; Rotter, J.I.; Beiser, A.S.; Maniega, S.M.; Beekman, M.; Trollor, J.; Stott, D.J.; Vernooij, M.W.; Wittfeld, K.; Niessen, W.J.; Soumare, A.; Boerwinkle, E.; Sidney, S.; Turner, S.T.; Davies, G.; Thalamuthu, A.; Volker, U.; Buchem, M.A. van; Bryan, R.N.; Dupuis, J.; Bastin, M.E.; Ames, D.; Teumer, A.; Amouyel, P.; Kwok, J.B.; Bulow, R.; Deary, I.J.; Schofield, P.R.; Brodaty, H.; Jiang, J.Y.; Tabara, Y.; Setoh, K.; Miyamoto, S.; Yoshida, K.; Nagata, M.; Kamatani, Y.; Matsuda, F.; Psaty, B.M.; Bennett, D.A.; Jager, P.L. de; Mosley, T.H.; Sachdev, P.S.; Schmidt, R.; Warren, H.R.; Evangelou, E.; Tregouet, D.A.; Ikram, M.A.; Wen, W.; DeCarli, C.; Srikanth, V.K.; Jukema, J.W.; Slagboom, E.P.; Kardia, S.L.R.; Okada, Y.; Mazoyer, B.; Wardlaw, J.M.; Nyquist, P.A.; Mather, K.A.; Grabe, H.J.; Schmidt, H.; Duijn, C.M. van; Gudnason, V.; Longstreth, W.T.; Launer, L.J.; Lathrop, M.; Seshadri, S.; Tzourio, C.; Adams, H.H.; Matthews, P.M.; Fornage, M.; Debette, S.; Int Network Thrombosis INVENT Cons; Int Headache Genomics Consortium I
• Date: 2020-12-08
• Journal: Nature Communications
• Volume: 11
• Issue: 1
• DOI: doi:10.1038/s41467-020-19111-2
• Link: https://www.nature.com/articles/s41467-020-19111-2