Cerebral small vessel disease genomics and its implications across the lifespan
Muralidharan Sargurupremraj; Hideaki Suzuki; Xueqiu Jian; Chloé Sarnowski; Tavia E. Evans; Joshua C. Bis; Gudny Eiriksdottir; Saori Sakaue; Natalie Terzikhan; Mohamad Habes; Wei Zhao; Nicola J. Armstrong; Edith Hofer; Lisa R. Yanek; Saskia P. Hagenaars; Rajan B. Kumar; Erik B. van den Akker; Rebekah E. McWhirter; Stella Trompet; Aniket Mishra; Yasaman Saba; Claudia L. Satizabal; Gregory Beaudet; Laurent Petit; Ami Tsuchida; Laure Zago; Sabrina Schilling; Sigurdur Sigurdsson; Rebecca F. Gottesman; Cora E. Lewis; Neelum T. Aggarwal; Oscar L. Lopez; Jennifer A. Smith; Maria C. Valdés Hernández; Jeroen van der Grond; Margaret J. Wright; Maria J. Knol; Marcus Dörr; Russell J. Thomson; Constance Bordes; Quentin Le Grand; Marie-Gabrielle Duperron; Albert V. Smith; David S. Knopman; Pamela J. Schreiner; Denis A. Evans; Jerome I. Rotter; Alexa S. Beiser; Susana Muñoz Maniega; Marian Beekman; Julian Trollor; David J. Stott; Meike W. Vernooij; Katharina Wittfeld; Wiro J. Niessen; Aicha Soumaré; Eric Boerwinkle; Stephen Sidney; Stephen T. Turner; Gail Davies; Anbupalam Thalamuthu; Uwe Völker; Mark A. van Buchem; R. Nick Bryan; Josée Dupuis; Mark E. Bastin; David Ames; Alexander Teumer; Philippe Amouyel; John B. Kwok; Robin Bülow; Ian J. Deary; Peter R. Schofield; Henry Brodaty; Jiyang Jiang; Yasuharu Tabara; Kazuya Setoh; Susumu Miyamoto; Kazumichi Yoshida; Manabu Nagata; Yoichiro Kamatani; Fumihiko Matsuda; Bruce M. Psaty; David A. Bennett; Philip L. De Jager; Thomas H. Mosley; Perminder S. Sachdev; Reinhold Schmidt; Helen R. Warren; Evangelos Evangelou; David-Alexandre Trégouët; International Network against Thrombosis (INVENT) Consortium; International Headache Genomics Consortium (IHGC); Mohammad A. Ikram; Wei Wen; Charles DeCarli; Velandai K. Srikanth; J. Wouter Jukema; Eline P. Slagboom; Sharon L. R. Kardia; Yukinori Okada; Bernard Mazoyer; Joanna M. Wardlaw; Paul A. Nyquist; Karen A. Mather; Hans J. Grabe; Helena Schmidt; Cornelia M. Van Duijn; Vilmundur Gudnason; William T. Longstreth Jr; Lenore J. Launer; Mark Lathrop; Sudha Seshadri; Christophe Tzourio; Hieab H. Adams; Paul M. Matthews; Myriam Fornage; Stéphanie Debette
https://urn.fi/URN:NBN:fi-fe2021042824324
Tiivistelmä
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.
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