Genetic risk factors underlying white matter hyperintensities and cortical atrophy

Yash Patel, Jean Shin, Eeva Sliz, Ariana Tang, Aniket Mishra, Rui Xia, Edith Hofer, Hema Sekhar Reddy Rajula, Ruiqi Wang, Frauke Beyer, Katrin Horn, Max Riedl, Jing Yu, Henry Völzke, Robin Bülow, Uwe Völker, Stefan Frenzel, Katharina Wittfeld, Sandra Auwera, Thomas H. Mosley, Vincent Bouteloup, Jean-Charles Lambert, Geneviève Chêne, Carole Dufouil, Christophe Tzourio, Jean-François Mangin, Rebecca F. Gottesman, Myriam Fornage, Reinhold Schmidt, Qiong Yang, Veronica Witte, Markus Scholz, Markus Loeffler, Gennady V. Roshchupkin, M. Arfan Ikram, Hans J. Grabe, Sudha Seshadri, Stephanie Debette, Tomas Paus () and Zdenka Pausova ()
Additional contact information
Yash Patel: Toronto
Jean Shin: Toronto
Eeva Sliz: University of Oulu
Ariana Tang: Toronto
Aniket Mishra: UMR1219
Rui Xia: The University of Texas Health Science Center at Houston
Edith Hofer: Statistik und Dokumentation
Hema Sekhar Reddy Rajula: UMR1219
Ruiqi Wang: Boston University School of Public Health
Frauke Beyer: UMR1219
Katrin Horn: Statistics and Epidemiology; Leipzig University
Max Riedl: Statistics and Epidemiology; Leipzig University
Jing Yu: Erasmus MC University Medical Center Rotterdam
Henry Völzke: University Medicine Greifswald
Robin Bülow: University Medicine Greifswald
Uwe Völker: University Medicine Greifswald
Stefan Frenzel: University Medicine Greifswald
Katharina Wittfeld: University Medicine Greifswald
Sandra Auwera: University Medicine Greifswald
Thomas H. Mosley: The University of Mississippi Medical Center
Vincent Bouteloup: UMR1219
Jean-Charles Lambert: University of Lille
Geneviève Chêne: UMR1219
Carole Dufouil: UMR1219
Christophe Tzourio: UMR1219
Jean-François Mangin: Baobab
Rebecca F. Gottesman: National Institute of Neurological Disorders and Stroke Intramural Research Program
Myriam Fornage: The University of Texas Health Science Center at Houston
Reinhold Schmidt: Medical University of Graz
Qiong Yang: Boston University School of Public Health
Veronica Witte: Max Planck Institute for Human Cognitive and Brain Sciences
Markus Scholz: Statistics and Epidemiology; Leipzig University
Markus Loeffler: Statistics and Epidemiology; Leipzig University
Gennady V. Roshchupkin: Erasmus MC University Medical Center Rotterdam
M. Arfan Ikram: Erasmus MC University Medical Center Rotterdam
Hans J. Grabe: University Medicine Greifswald
Sudha Seshadri: University of Texas
Stephanie Debette: UMR1219
Tomas Paus: University of Montreal
Zdenka Pausova: Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Date: 2024
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DOI: 10.1038/s41467-024-53689-1

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