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Perivascular Space Genetic Study Points to Targets for Cerebral Small Vessel Disease Prevention

NEW YORK— An international team of researchers has mapped 24 genetic risk loci of perivascular space (PVS) burden, a marker of cerebral small vessel disease (cSVD), that suggest potential new drug targets for preventing the disease. 

Perivascular spaces are areas surrounding small vessel walls in the brain that increase with age and factors such as hypertension. They are also an early magnetic resonance imaging marker of cSVD, which in turn is a major cause of stroke and dementia but has no specific treatment to date.

While PVS burden is heritable to a large extent, its genetic determinants have been largely unknown, according to the authors.

For their study, published in Nature Medicine on Tuesday, the researchers analyzed GWAS data from more than 40,000 participants, of whom more than 9,000 had extensive PVS burden in the white matter, basal ganglia, or hippocampus. Participants included those from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and from the UK Biobank and were primarily of European descent.

In addition, the team — led by co-corresponding authors Hieab Adams of Erasmus MC University Medical Center in the Netherlands and Stéphanie Debette of the University of Bordeaux in France — analyzed whole-exome sequencing data and the exome portion of whole-genome sequencing data for more than 19,000 participants from the UK Biobank and the Brain Imaging, Cognition, Dementia, and Next-generation Genomics (BRIDGET) consortium, of whom around 4,500 had PVS on one of the three brain regions.

Overall, they found 24 genetic risk loci for PVS, mostly those in white matter. The researchers also noted that most white matter PVS loci reached nominally significant associations with PVS in a follow-up study involving almost 2,900 older Japanese individuals and were already associated with white matter PVS in a cohort of more than 1,700 young adults. "Our results are an important initial step to establish the generalizability of cSVD genetic associations across ancestries," the authors wrote.

They added, however, that there is a need to include more data from African American populations in the future in whom cSVD is more frequent.

"Interestingly two-thirds of PVS risk loci point to pathways that were not mediated by established risk factors, involving extracellular matrix, blood-brain barrier, membrane transport, and vascular development," Debette wrote in an email.

Meanwhile, they also found that the PVS risk loci were enriched in genes involved in early-onset leukodystrophies and in genes expressed in fetal brain vascular endothelial cells.

Further transcriptome-wide association studies revealed 12 genes the researchers plan to prioritize for functional follow-up, including targets of drugs investigated for vascular and cognitive disorders.

The findings also showed genetic associations between blood pressure and basal ganglia as well as hippocampal PVS, and between stroke and those PVS.

According to the authors, with the development of artificial intelligence-based computational methods for PVS quantification, future genomic studies will likely have even greater power to detect genetic associations.

Already, the results could have implications for the prevention of cSVD. "Our findings provide insight into the biology of PVS across the adult lifespan and its contribution to cSVD pathophysiology, with potential for genetically informed prioritization of drug targets for prevention trials of cSVD," they wrote.