Abstract / Summary
Background Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke and premature mortality, with higher prevalence in specific ethnic groups. Multiple studies have evaluated the association of ICAD and genetic variants. This study aims to systematically review and summarize the current genetic contributors of ICAD. Methods Systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Embase, MEDLINE, and Cochrane Library databases were searched from inception to September 2025 for human studies examining single‐nucleotide variants (SNVs) associations and ICAD. Three independent reviewers extracted data on study characteristics, SNVs, alleles and P values. SNVs reported in >1 study were pooled using a fixed‐effects model. Expression quantitative trait loci analysis evaluated the regulatory effects of identified SNVs across brain and arterial tissue. Functional enrichment analysis was conducted to identify relevant biological pathways. Results Fourteen studies met inclusion criteria, comprising a total of 15 535 individuals, of whom 3638 had ICAD. Across these studies, 35 SNVs were identified, mapping to 26 unique genes. In the pooled analysis, ICAD was associated with RNF213 rs112735431 (odds ratio, 18.61 [95% CI, 11.84–29.25]). Other SNVs were found in genes including ADIPOQ , INSR , and NTNG1 . Functional enrichment highlighted lipid metabolism and triglyceride homeostasis pathways as key contributors to ICAD risk. Conclusions This review consolidates current evidence on SNVs associated with ICAD, highlighting RNF213 rs112735431 as a major genetic contributor, particularly in East Asian populations. Further research is needed to clarify the functional roles of these variants and their potential as therapeutic targets.