A leading cause of stroke and cognitive decline, mapped by a 2022 study of over 41,000 people that found 11 risk loci and traced one, TRIM47, all the way to a lab experiment on brain blood vessels.
Cerebral small vessel disease (CSVD) is a leading cause of stroke and a major contributor to cognitive decline and dementia. Much of its genetic basis has been hard to pin down — this page covers five variants from the largest gene-mapping effort against it to date.
A 2022 study in Brain built a genome-wide association study and a separate whole-exome association study around a composite "extreme phenotype" of CSVD, defined from its two most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older adults contributed the data — 41,326 people with genome-wide genotyping (13,776 with the extreme phenotype) for the GWAS, and 15,965 with whole-exome sequencing plus 5,249 with exome-chip data (7,079 with the extreme phenotype) for the exome study.
The GWAS identified significant association at 11 genomic loci. Five of them are catalogued on this page: rs3744027 (TRIM65), rs6503417 (NMT1), rs12149643 (C16orf95), rs73191849 (PPTC7), and rs13403122 (near HAAO).
The same paper's whole-exome arm, run separately from the GWAS above, highlighted a different gene, TRIM47, along with EFEMP1 — neither is among the five variants on this page. The authors followed TRIM47 up with laboratory work: its expression in brain blood vessels ran inversely with disease severity, it was enriched in isolated brain-vessel tissue from mice, and reducing it in human brain endothelial cells (via siRNA knockdown) increased how permeable those cells were — a hallmark of CSVD pathology. The study also used Mendelian randomization to show that more extensive small-vessel disease causally raises the risk of both stroke and Alzheimer's disease.
Cerebral small vessel disease is diagnosed by MRI (white matter hyperintensities, lacunes) and clinical assessment, not by genotype. These five variants are risk-locus findings from a large gene-mapping study, not diagnostic markers.
The study's Mendelian randomization result — that greater small-vessel disease severity causally increases stroke and Alzheimer's risk — is a population-level finding about the disease process itself, not something read off any one person's genotype at these five loci.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Cerebral Small Vessel Disease comes down to these specific, well-studied positions — not a diagnosis.
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Cerebral Small Vessel Disease. MyGeneLog™. https://www.mygenelog.com/conditions/cerebral-small-vessel-disease
Cerebral small vessel disease (CSVD) is a leading cause of stroke and a major contributor to cognitive decline and dementia, affecting the brain’s smallest blood vessels.
No. TRIM47 was identified in the same 2022 study, but through a separate whole-exome analysis, not the genome-wide analysis the five variants on this page come from.
The same study found, using Mendelian randomization, that more extensive small vessel disease causally increases the risk of both stroke and Alzheimer’s disease.
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