Cerebral small vessel disease genomics and its implications across the lifespan
Authors: Sargurupremraj Muralidharan , Suzuki Hideaki , Jian Xueqiu , Sarnowski Chloé , Evans Tavia E. , Bis Joshua C. , Eiriksdottir Gudny , Sakaue Saori , Terzikhan Natalie , Habes Mohamad , Zhao Wei , Armstrong Nicola J. , Hofer Edith , Yanek Lisa R. , Hagenaars Saskia P. , Kumar Rajan B. , van den Akker Erik B. , McWhirter Rebekah E. , Trompet Stella , Mishra Aniket , Saba Yasaman , Satizabal Claudia L. , Beaudet Gregory , Petit Laurent , Tsuchida Ami , Zago Laure , Schilling Sabrina , Sigurdsson Sigurdur , Gottesman Rebecca F. , Lewis Cora E. , Aggarwal Neelum T. , Lopez Oscar L. , Smith Jennifer A. , Valdés Hernández Maria C. , van der Grond Jeroen , Wright Margaret J. , Knol Maria J. , Dörr Marcus , Thomson Russell J. , Bordes Constance , Le Grand Quentin , Duperron Marie-Gabrielle , Smith Albert V. , Knopman David S. , Schreiner Pamela J. , Evans Denis A. , Rotter Jerome I. , Beiser Alexa S. , Maniega Susana Muñoz , Beekman Marian , Trollor Julian , Stott David J. , Vernooij Meike W. , Wittfeld Katharina , Niessen Wiro J. , Soumaré Aicha , Boerwinkle Eric , Sidney Stephen , Turner Stephen T. , Davies Gail , Thalamuthu Anbupalam , Völker Uwe , van Buchem Mark A. , Bryan R. Nick , Dupuis Josée , Bastin Mark E. , Ames David , Teumer Alexander , Amouyel Philippe , Kwok John B. , Bülow Robin , Deary Ian J. , Schofield Peter R. , Brodaty Henry , Jiang Jiyang , Tabara Yasuharu , Setoh Kazuya , Miyamoto Susumu , Yoshida Kazumichi , Nagata Manabu , Kamatani Yoichiro , Matsuda Fumihiko , Psaty Bruce M. , Bennett David A. , De Jager Philip L. , Mosley Thomas H. , Sachdev Perminder S. , Schmidt Reinhold , Warren Helen R. , Evangelou Evangelos , Trégouët David-Alexandre ,   International Network against Thrombosis (INVENT) Consortium, Amouyel Philippe , de Andrade Mariza , Basu Saonli , Berr Claudine , Brody Jennifer A. , Chasman Daniel I. , Dartigues Jean-Francois , Folsom Aaron R. , Germain Marine , de Haan Hugoline , Heit John , Houwing-Duitermaat Jeanine , Kabrhel Christopher , Kraft Peter , Legal Grégoire , Lindström Sara , Monajemi Ramin , Morange Pierre-Emmanuel , Psaty Bruce M. , Reitsma Pieter H. , Ridker Paul M. , Rose Lynda M. , Rosendaal Frits R. , Saut Noémie , Slagboom Eline , Smadja David , Smith Nicholas L. , Suchon Pierre , Tang Weihong , Taylor Kent D. , Trégouët David-Alexandre , Tzourio Christophe , de Visser Marieke C. H. , van Hylckama Vlieg Astrid , Weng Lu-Chen , Wiggins Kerri L. ,   International Headache Genomics Consortium (IHGC), Gormley Padhraig , Anttila Verneri , Winsvold Bendik S. , Palta Priit , Esko Tonu , Pers Tune H. , Farh Kai-How , Cuenca-Leon Ester , Muona Mikko , Furlotte Nicholas A. , Kurth Tobias , Ingason Andres , McMahon George , Ligthart Lannie , Terwindt Gisela M. , Kallela Mikko , Freilinger Tobias M. , Ran Caroline , Gordon Scott G. , Stam Anine H. , Steinberg Stacy , Borck Guntram , Koiranen Markku , Quaye Lydia , Adams Hieab H. H. , Lehtimäki Terho , Sarin Antti-Pekka , Wedenoja Juho , Hinds David A. , Buring Julie E. , Schürks Markus , Ridker Paul M. , Gudlaug Hrafnsdottir Maria , Stefansson Hreinn , Ring Susan M. , Hottenga Jouke-Jan , Penninx Brenda W. J. H. , Färkkilä Markus , Artto Ville , Kaunisto Mari , Vepsäläinen Salli , Malik Rainer , Heath Andrew C. , Madden Pamela A. F. , Martin Nicholas G. , Montgomery Grant W. , Kurki Mitja , Kals Mart , Mägi Reedik , Pärn Kalle , Hämäläinen Eija , Huang Hailiang , Byrnes Andrea E. , Franke Lude , Huang Jie , Stergiakouli Evie , Lee Phil H. , Sandor Cynthia , Webber Caleb , Cader Zameel , Muller-Myhsok Bertram , Schreiber Stefan , Meitinger Thomas , Eriksson Johan G. , Salomaa Veikko , Heikkilä Kauko , Loehrer Elizabeth , Uitterlinden Andre G. , Hofman Albert , van Duijn Cornelia M. , Cherkas Lynn , Pedersen Linda M. , Stubhaug Audun , Nielsen Christopher S. , Männikkö Minna , Mihailov Evelin , Milani Lili , Göbel Hartmut , Esserlind Ann-Louise , Francke Christensen Anne , Folkmann Hansen Thomas , Werge Thomas , Kaprio Jaakko , Aromaa Arpo J. , Raitakari Olli , Ikram M. Arfan , Spector Tim , Järvelin Marjo-Riitta , Metspalu Andres , Kubisch Christian , Strachan David P. , Ferrari Michel D. , Belin Andrea C. , Dichgans Martin , Wessman Maija , van den Maagdenberg Arn M. J. M. , Zwart John-Anker , Boomsma Dorret I. , Davey Smith George , Stefansson Kari , Eriksson Nicholas , Daly Mark J. , Neale Benjamin M. , Olesen Jes , Chasman Daniel I. , Nyholt Dale R. , Palotie Aarno , Ikram Mohammad A. , Wen Wei , DeCarli Charles , Srikanth Velandai K. , Jukema J. Wouter , Slagboom Eline P. , Kardia Sharon L. R. , Okada Yukinori , Mazoyer Bernard , Wardlaw Joanna M. , Nyquist Paul A. , Mather Karen A. , Grabe Hans J. , Schmidt Helena , Van Duijn Cornelia M. , Gudnason Vilmundur , Longstreth William T. , Launer Lenore J. , Lathrop Mark , Seshadri Sudha , Tzourio Christophe , Adams Hieab H. , Matthews Paul M. , Fornage Myriam , Debette Stéphanie 
Published: December 2020

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.