Unravelling the genetic architecture of cerebral small vessel disease in the context of stroke.

Cerebral small vessel disease (cSVD) is a major contributor to stroke, dementia, and cognitive decline. Despite significant progress through large-scale genome-wide association studies (GWAS) for cSVD and stroke, the genetic architecture underlying these conditions remains poorly understood. This review highlights recent advancements in statistical tools and provides a comprehensive overview of current insights into the genetic underpinnings of cSVD and stroke. We focus on the relevance of non-additive effects, local heritability, and polygenicity in shaping these traits. While single nucleotide polymorphism (SNP)-based heritability estimates for stroke and cSVD traits remain lower than pedigree-based estimates, we explore challenges and opportunities in addressing this "missing heritability." In particular, we emphasize the importance of investigating both common and rare variants, to better characterize the genetic basis of cSVD. Furthermore, we discuss the role of negative selection in shaping complex disease traits and the relevance of the "omnigenic" model in the context of cSVD traits. In summary, we aim to provide a more nuanced understanding of cSVD and stroke genetics, paving the way for future research into their molecular mechanisms.