Genomics of diffusion-imaging integrating GWAS, exome data and single-cell sequencing unravels lifespan determinants of cerebral small vessel disease
Authors: Debette Stephanie , Saba Yasaman , Suzuki Hideaki , Maillard Pauline , Tankard Rick , Luciano Michelle , Caro Ilana , Jahanshad Neda , Duering Marco , Beyer Frauke , Bai Wenjia , Glavan Martina , Grand Quentin Le , Teumer Alexander , Lemaitre Hervé , Sargurupremraj Muralidharan , Duperron Marie-Gabrielle , Adams Hieab , Aparicio Hugo , Arfanakis Konstantinos , Armstrong Nicola J. , Bryan Nick , Bastin Mark , Beiser Alexa , Bennett David , Bhatt Ravi , Bourque Guillaume , Brodaty Henry , Cichon Sven , Colling Amelie , Deary Ian , Enzinger Christian , Forsberg Lars , Gampawar Piyush , Gottesman Rebecca , Gudmundsdottir Val borg , Habes Mohamad , Hachiya Tsuyoshi , Hofer Edith , Hsu Justine , Ikram Mohammad , Imtiaz M. , Islam Tasfiya , Jiang Jiyang , Kawaguchi Takahisa , Kinoshita Kengo , Knol Maria , Koch Alexandra , Kojima You , Lathrop Mark , Leurgans Sue , Matsuda Fumihiko , Mori Naoko , Mosley Thomas , Motoike Ikuko , Mugikura Shunji , Nasrallah Ilya , Nir Talia , Patel Yash , Prendergast James , Romero Jose , Sachdev Perminder , Satizabal Claudia , Scholz Markus , Sheth Kevin , Shin Jean , Sigurdsson Sigurdur , Thalamuthu Anbupalam , Trollor Julian , Tsuchida Ami , Villringer Arno , Wardlaw Joanna , Wen Wei , Yang Jingyun , Yang Qiong , Zhang Menglei , Zhu Alyssa , Mühleisen Thomas , Mather Karen , Do Ron , Pausova Zdenka , De Jager Philip , Crivello Fabrice , Caspers Svenja , Witte Veronica , Tzourio Christophe , Tilgner Hagen , Sestan Nenad , Roshchupkin Gennady , Paus Tomasi , Seshadri Sudha , Fornage Myriam , DeCarli Charles , Launer Lenore , Schmidt Helena , Gudnason Vilmundur , Matthews Paul , Breteler Monique , Mishra Aniket 
Published: February 2025

Abstract

Peak width of skeletonized mean diffusivity (PSMD) is an emerging automated diffusion imaging marker showing clinically relevant changes in cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no mechanism-based treatment. We conducted a genome-wide association study of PSMD in 58,403 participants from 24 population-based cohorts (89% European, 10% East-Asian, 1% African-American), identifying 31 independent common variant associations. Additionally, a whole-exome sequencing analysis in 32,957 participants yielded associations of PSMD with single and burden of rare coding variants in four novel genes. Mendelian randomization supported causal association of higher blood pressure with larger PSMD values, and of larger PSMD with an increased risk of stroke, especially intracerebral hemorrhage. Strikingly, genetic susceptibility to white matter hyperintensities, an established MRI-marker of cSVD, was associated with higher PSMD from early childhood to older age, with prominent lifespan effects for VCAN and SMG6. Leveraging unique brain single-cell sequencing resources we showed temporal changes in the cell-type specificity of these genes in the developing brain and overall enrichment of PSMD risk loci in genes expressed in fetal brain endothelial cells. Finally, through extensive integration with multi-omics resources, we provide precious leads for gene prioritization to accelerate drug discovery for cSVD.