Background: White matter hyperintensities (WMHs) are important markers of cerebral small vessel disease (CSVD), associated with heightened risks of stroke and dementia. WMH are classified into two subtypes according to region: Periventricular WMH (PVWMH) and deep WMH (DWMH), reflecting proposed differences in cause.
Methods: GWAS for PVWMH and DWMH were conducted using UKB participants aged 45 years and older, free of stroke, dementia and other major brain abnormalities (n=58,909). Regional correlations were investigated using the GWAS-PW method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Causal variants in genomic risk loci were identified using SuSiE fine-mapping methods.
Results: We identified significant associations for PVWMH on chromosomes 13 (COL4A2), 15 (RASL12), and 17 (B9D1), as well as 25 loci unique to PVWMH, including chromosomes 6 (with six regions), 10 (with three regions), and 14 (with three regions). For DWMH, significant associations were identified on chromosomes 12 (PAWR), 19 (APOE) and 22 (LIMK2), as well as 18 loci unique to DWMH, including chromosomes 1 (with five regions) and 19 (with two regions). Using gene-based association analysis, 43 genes across all regions were identified for PVWMH only, including HEXIM2 (chromosome 17), VCAN (chromosome 5), and C16orf95 (chromosome 16). Unique to DWMH were 37 genes, including ACTN4 (chromosome 19), DRG1, and LIMK2 (chromosome 22). Forty-nine genes across all regions were identified as significant for both phenotypes.
Conclusion: PVWMH and DWMH show distinct genetic bases, confirming previous findings and the relevance of chromosome 17 risk loci. The number of independent loci identified for PVWMH increased from 11 to 25 and for DWMH from 1 to 18, highlighting new genes such as RASL12 (PVWMH) and LIMK2 (DWMH). Future research will focus on these genes and loci, seeking to replicate earlier results through meta-analysis.