Genetic risk factors underlying white matter hyperintensities and cortical atrophy
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.
Authors
- Jean‐Charles Lambert (ORCID: https://orcid.org/0000-0003-0829-7817)
- Stefan Frenzel (ORCID: https://orcid.org/0000-0001-5087-5970)
- Tomáš Paus (ORCID: https://orcid.org/0000-0003-1495-9338)
- Sudha S. Seshadri (ORCID: https://orcid.org/0000-0001-6135-2622)
- Aniket Mishra (ORCID: https://orcid.org/0000-0002-8141-1543)
- Ruiqi Wang
- Katrin Horn (ORCID: https://orcid.org/0000-0002-5307-6936)
- Rui Xia (ORCID: https://orcid.org/0000-0003-2409-1181)
- Markus Loeffler (ORCID: https://orcid.org/0000-0002-0424-9933)
- Zdenka Pausová (ORCID: https://orcid.org/0000-0002-7784-1380)
- Robin Bülow (ORCID: https://orcid.org/0000-0003-1884-5784)
- Gennady V. Roshchupkin (ORCID: https://orcid.org/0000-0002-3403-2313)
- M. Arfan Ikram (ORCID: https://orcid.org/0000-0003-0372-8585)
- Hans Jörgen Grabe (ORCID: https://orcid.org/0000-0003-3684-4208)
- A. Veronica Witte (ORCID: https://orcid.org/0000-0001-9054-6688)
- Rebecca F. Gottesman (ORCID: https://orcid.org/0000-0002-9504-1256)
- Jing Yu (ORCID: https://orcid.org/0000-0001-7752-9971)
- Hema Sekhar Reddy Rajula (ORCID: https://orcid.org/0000-0003-4667-8143)
- Christophe Tzourio (ORCID: https://orcid.org/0000-0002-6517-2984)
- Carole Dufouil (ORCID: https://orcid.org/0000-0003-2442-4476)
- Jean Shin (ORCID: https://orcid.org/0000-0001-7353-5178)
- Markus Scholz (ORCID: https://orcid.org/0000-0002-4059-1779)
- Sandra Van der Auwera (ORCID: https://orcid.org/0000-0002-1757-7768)
- Katharina Wittfeld (ORCID: https://orcid.org/0000-0003-4383-5043)
- Stéphanie Debette (ORCID: https://orcid.org/0000-0001-8675-7968)
- Geneviève Chêne (ORCID: https://orcid.org/0000-0002-8368-6460)
- Frauke Beyer (ORCID: https://orcid.org/0000-0001-5401-852X)
- Eeva Sliz (ORCID: https://orcid.org/0000-0002-2316-058X)
- Uwe Völker (ORCID: https://orcid.org/0000-0002-5689-3448)
- Vincent Bouteloup (ORCID: https://orcid.org/0009-0008-9956-862X)
- Myriam Fornage (ORCID: https://orcid.org/0000-0003-0677-8158)
- Yash Patel (ORCID: https://orcid.org/0000-0002-5993-2772)
- Qiong Yang (ORCID: https://orcid.org/0000-0002-3658-1375)
- Edith Hofer
- Thomas H. Mosley
- Maureen Riedl
- Henry Völzke
- Ariana Tang
- Jean-François Mangin
- Reinhold Schmidt
Institutions
- Université du Québec à Chicoutimi (CA)
- Boston University (US)
- Centre National de la Recherche Scientifique (FR)
- Statistics Austria (AT)
- Leipzig University of Applied Sciences (DE)
- Université de Bordeaux (FR)
- Inserm (FR)
- University of Toronto (CA)
- Medical University of Graz (AT)
- Université de Lille (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Universitätsmedizin Greifswald (DE)
- Institut Pasteur de Lille (FR)
- Hospital for Sick Children (CA)
- German Center for Neurodegenerative Diseases (DE)
- Erasmus MC (NL)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Jackson Memorial Hospital (US)
- University of Mississippi Medical Center (US)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Institut des Maladies Neurodégénératives (FR)
- Bordeaux Population Health (FR)
- National Institute of Neurological Disorders and Stroke (US)
- University Hospital Leipzig (DE)
- CEA Paris-Saclay (FR)
- Max Planck Institute for Human Cognitive and Brain Sciences (DE)
- Brown Foundation (US)
- Institute for Medical Informatics and Biostatistics (CH)
- The University of Texas at San Antonio (US)
- McGill University (CA)
- Université de Montréal (CA)
- The University of Texas Health Science Center at Houston (US)
- Leipzig University (DE)
- University of Oulu (FI)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1038/s41467-024-53689-1
- Citations
- 12
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 3.92
Funders
- Université de Bordeaux
- National Institutes of Health
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute on Deafness and Other Communication Disorders
- National Institute of Neurological Disorders and Stroke