Cross-phenotype and cross-species integrative genomic prioritization of FOXF2 and FOXC1 at a cerebral small vessel disease locus.
Cerebral small vessel disease (CSVD) is genetically heterogeneous, and translating regional association signals into biologically plausible effector-gene hypotheses remains challenging. We performed a cross-phenotype and cross-species integrative genomic analysis of the FOXF2-centered proximal chromosome 6 region using publicly available genome-wide association study summary statistics for lacunar stroke, small-vessel disease ischemic stroke subtype and white matter hyperintensity volume. The chr6:0-2.5 Mb interval was treated as the primary regional analysis, whereas FOXF2 ± 1 Mb and FOXF2 ± 500 kb were examined as nested sensitivity windows. Linkage disequilibrium, regional gene annotation, quantitative trait locus evidence, colocalization, fine-mapping, GWAS Catalog records and human and mouse brain vascular transcriptomic data were integrated within a predefined candidate-prioritization framework. Lacunar stroke showed the strongest regional evidence, with rs7766042 meeting the predefined broad-window local correction threshold, although no signal reached conventional genome-wide significance. The SVD ischemic stroke subtype and WMH signals did not meet their corresponding local correction thresholds. Phenotype-specific lead variants showed low pairwise linkage disequilibrium, a pattern consistent with regional signal heterogeneity but not sufficient to establish distinct causal signals. FOXF2 and FOXC1 were prioritized as leading neurovascular candidates, whereas EXOC2 and GMDS were retained as secondary positional candidates. Several regional variants overlapped FOXF2 eQTL annotations; however, formal colocalization showed little evidence for a shared causal variant (PP.H4 = 0.0604), and fine-mapping did not resolve a single causal variant. Human and mouse brain vascular transcriptomic analyses provided cross-species expression-based cellular context for FOXF2 and FOXC1. These findings support regional candidate-gene prioritization at the proximal chromosome 6 locus while emphasizing that the available evidence does not establish a definitive multi-signal or multi-gene causal architecture.