Genetics of Small Vessel Disease

Cerebral small vessel disease (CSVD) is highly prevalent in the general population and is overall a leading cause of disability. CSVD manifestations span from clinical events such as ischemic strokes, intracerebral hemorrhages, and vascular dementia to imaging features such as white matter hyperintensities, lacunar infarcts, microbleeds, and enlarged perivascular spaces. Familial diseases that are characterized by co-occurrence of multiple manifestations of CSVD, heritability of sporadic forms of CSVD, and robust associations between genes and various features of sporadic CSVD, all suggest the key role that genetics can have in understanding the disease. Here, we initially recapitulate the most recent genome-wide association studies that have identified genes and the loci associated with the sporadic clinical and neuroimaging manifestations of CSVD. Then, we examine the familial diseases that feature the same CSVD manifestations and their causal genes, such as NOTCH3 and collagen genes. Lastly, we review the data that support the involvement of the genes for familial disease in sporadic CSVD manifestations. From the combination of these perspectives, we can detect the genes and the correspondent pathological pathways, which can help us understand the disease. We highlight the future endeavors of the scientific community to achieve this aim and to eventually prompt new therapies.