Abstract Background and aims White matter hyperintensity (WMH) is the most common MRI features of cerebral small vessel disease (CSVD), associated with increased risk of stroke and dementia. Despite high burden of CSVD in China, the genetic risk architecture of WMH burden is underexplored. We report a largest genetic association study on WMH burden using two Chinese older adult cohorts. Methods The whole-genome sequencing data of 781 participants of National Brain Ageing Cohort and genome-wide genotyping data imputed using 1000G reference of 971 participants of Shunyi Cohort was used in this investigation. The total WMH volume was derived from 3T MRI in both cohorts using similar protocols. Association tests were performed using REGENIE software considering mixed-linear model adjusting for age, age2, sex, principal components, and total intracranial volume. To enhance genetic discovery, we meta-analyzed association statistics from individual cohorts using METAL software. Results Our top association at 12p12.3 near AEBP2 (rs6486999-G, AF=0.49, beta(SE)=0.131(0.025); P=9.684e-08) reached a borderline genome-wide significance. Of 27 known WMH risk loci in Europeans, 17 showed concordant direction of effect in Chinese population. Of these, 2 loci at VCAN (5q14.3, rs17205972-T, beta(SE)=0.081(0.027); p-value=0.003) and at PKN2 (1p21.3, rs786921-A, beta(SE)=0.050(0.025) ; p-value=0.044) showed p-value0.05. Conclusions We report the largest genetic association study on WMH volume in Chinese population, identifying 1 novel hit at borderline genome-wide significance threshold. Our findings show concordant direction of effects for known WMH risk loci identified in Europeans. Inclusion of additional Chinese sample in our study is ongoing. Conflict of interest Dingding Zhang: nothing to disclose. Xinzhuang Yang: nothing to disclose. Li Li: nothing to disclose. Fei Han: nothing to disclose. Ziyue Liu: nothing to disclose. Xingqi Pan: nothing to disclose. Aniket Mishra: nothing to disclose. Stephanie Debette: nothing to disclose. Yicheng Zhu: nothing to disclose. Figure 1 - belongs to Conclusions
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