TY - JOUR
T1 - Cerebral small vessel disease genomics and its implications across the lifespan
AU - Sargurupremraj, Muralidharan
AU - Suzuki, Hideaki
AU - Jian, Xueqiu
AU - Sarnowski, Chloé
AU - Evans, Tavia E.
AU - Bis, Joshua C.
AU - Eiriksdottir, Gudny
AU - Sakaue, Saori
AU - Terzikhan, Natalie
AU - Habes, Mohamad
AU - Zhao, Wei
AU - Armstrong, Nicola J.
AU - Hofer, Edith
AU - Yanek, Lisa R.
AU - Hagenaars, Saskia P.
AU - Kumar, Rajan B.
AU - Van Den Akker, Erik B.
AU - Mcwhirter, Rebekah E.
AU - Trompet, Stella
AU - Mishra, Aniket
AU - Saba, Yasaman
AU - Satizabal, Claudia L.
AU - Beaudet, Gregory
AU - Petit, Laurent
AU - Tsuchida, Ami
AU - Zago, Laure
AU - Schilling, Sabrina
AU - Sigurdsson, Sigurdur
AU - Gottesman, Rebecca F.
AU - Lewis, Cora E.
AU - Aggarwal, Neelum T.
AU - Lopez, Oscar L.
AU - Smith, Jennifer A.
AU - Valdés Hernández, Maria C.
AU - Van Der Grond, Jeroen
AU - Wright, Margaret J.
AU - Knol, Maria J.
AU - Dörr, Marcus
AU - Thomson, Russell J.
AU - Bordes, Constance
AU - Le Grand, Quentin
AU - Duperron, Marie-gabrielle
AU - Smith, Albert V.
AU - Knopman, David S.
AU - Schreiner, Pamela J.
AU - Evans, Denis A.
AU - Rotter, Jerome I.
AU - Beiser, Alexa S.
AU - Maniega, Susana Muñoz
AU - Beekman, Marian
AU - Trollor, Julian
AU - Stott, David J.
AU - Vernooij, Meike W.
AU - Wittfeld, Katharina
AU - Niessen, Wiro J.
AU - Soumaré, Aicha
AU - Boerwinkle, Eric
AU - Sidney, Stephen
AU - Turner, Stephen T.
AU - Davies, Gail
AU - Thalamuthu, Anbupalam
AU - Völker, Uwe
AU - Van Buchem, Mark A.
AU - Bryan, R. Nick
AU - Dupuis, Josée
AU - Bastin, Mark E.
AU - Ames, David
AU - Teumer, Alexander
AU - Amouyel, Philippe
AU - Kwok, John B.
AU - Bülow, Robin
AU - Deary, Ian J.
AU - Schofield, Peter R.
AU - Brodaty, Henry
AU - Jiang, Jiyang
AU - Tabara, Yasuharu
AU - Setoh, Kazuya
AU - Miyamoto, Susumu
AU - Yoshida, Kazumichi
AU - Nagata, Manabu
AU - Kamatani, Yoichiro
AU - Matsuda, Fumihiko
AU - Psaty, Bruce M.
AU - Bennett, David A.
AU - De Jager, Philip L.
AU - Mosley, Thomas H.
AU - Sachdev, Perminder S.
AU - Schmidt, Reinhold
AU - Warren, Helen R.
AU - Evangelou, Evangelos
AU - Trégouët, David-alexandre
AU - Ikram, Mohammad A.
AU - Wen, Wei
AU - Decarli, Charles
AU - Srikanth, Velandai K.
AU - Jukema, J. Wouter
AU - Slagboom, Eline P.
AU - Kardia, Sharon L. R.
AU - Okada, Yukinori
AU - Mazoyer, Bernard
AU - Wardlaw, Joanna M.
AU - Nyquist, Paul A.
AU - Mather, Karen A.
AU - Grabe, Hans J.
AU - Schmidt, Helena
AU - Van Duijn, Cornelia M.
AU - Gudnason, Vilmundur
AU - Longstreth, William T.
AU - Launer, Lenore J.
AU - Lathrop, Mark
AU - Seshadri, Sudha
AU - Tzourio, Christophe
AU - Adams, Hieab H.
AU - Matthews, Paul M.
AU - Fornage, Myriam
AU - Debette, Stéphanie
AU - International Headache Genetics Consortium
AU - Ligthart, Lannie
AU - Boomsma, Dorret
AU - Hottenga, Jouke Jan
PY - 2020/12/8
Y1 - 2020/12/8
N2 - 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 = 2.5×10-7) 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.
AB - 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 = 2.5×10-7) 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.
U2 - 10.1038/s41467-020-19111-2
DO - 10.1038/s41467-020-19111-2
M3 - Article
VL - 11
SP - 1
EP - 18
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6285
ER -