Genetic risk factors underlying white matter hyperintensities and cortical atrophy.

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      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
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      Original Publication: [London] : Nature Pub. Group
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    • 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.
      (© 2024. The Author(s).)
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    • Grant Information:
      RF1 AG059421 United States AG NIA NIH HHS; 75N92022D00002 United States HL NHLBI NIH HHS; U01 HL096917 United States HL NHLBI NIH HHS; U01 HL096902 United States HL NHLBI NIH HHS; U01 AG058589 United States AG NIA NIH HHS; U01 HL096814 United States HL NHLBI NIH HHS; 75N92022D00005 United States HL NHLBI NIH HHS; U01 HL096899 United States HL NHLBI NIH HHS; 75N92022D00001 United States HL NHLBI NIH HHS; R01 AG056726 United States AG NIA NIH HHS; U01 HL096812 United States HL NHLBI NIH HHS; R01 NS017950 United States NS NINDS NIH HHS; U01 AG070112 United States AG NIA NIH HHS; 75N92022D00004 United States HL NHLBI NIH HHS; P30 AG066546 United States AG NIA NIH HHS; 75N92022D00003 United States HL NHLBI NIH HHS
    • Publication Date:
      Date Created: 20241104 Date Completed: 20241104 Latest Revision: 20241107
    • Publication Date:
      20241108
    • Accession Number:
      PMC11535513
    • Accession Number:
      10.1038/s41467-024-53689-1
    • Accession Number:
      39496600