Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study

• DOI: 10.1161/strokeaha.117.017430
• Publication Date: 2017-12-22T19:11:22Z
• Authors: Lian Duan; Ling Wei; Yanghua Tian; Zhengshan Zhang; Panpan Hu; Qiang Wei; Sugang Liu; Jun Zhang; Yuyang Wang; Desheng Li; Weizhong Yang; Rui Zong; Peng Xian; Cong Han; Xiangyang Bao; Feng Zhao; Jie Feng; Wei Liu; Wuchun Cao; Guoping Zhou; Chunyan Zhu; Fengqiong Yu; Weimin Yang; Yu Meng; Jingye Wang; Xianwen Chen; Yu Wang; Bing Shen; Bing Zhao; Jinghai Wan; Fengyu Zhang; Gang Zhao; Aimin Xu; Xuejun Zhang; Jianjun Liu; Xianbo Zuo; Kai Wang
• Keywords: Genome-wide Association Study; SNP; Genetic Association; Moyamoya Disease

Moyamoya disease (MMD) is a rare cerebral vasculopathy characterized by bilateral internal carotid artery stenosis and often leads to stroke in children or young adults. Although familial inheritance well recognized, the genetic basis of MMD remains poorly understood.A 2-stage genome-wide association study was conducted involving 1492 cases 5084 controls. In discovery stage, logistic regression used test associations, imputation based on genotyped single-nucleotide polymorphisms (SNPs). validation top significant SNPs were again an independent cohort. Fixed-effects inverse variance-weighted meta-analysis combined samples. Furthermore, analysis subgroups using patient clinical data.The identified 10 novel risk loci with significance (P<5×10-8) confirmed previously reported locus 17q25. No SNP showed evidence heterogeneity between 2 stages. Cumulatively, these explained 14.76% variance-a substantial proportion 39.02% variance all SNPs. One SNP, rs9916351 RNF213 (Pcombined=4.57×10-54; odds ratio, 1.96), stronger effect early-onset than late-onset (P=0.003). Two genes regulating homocysteine metabolism, rs9651118 MTHFR (Pcombined=2.49×10-19; 0.65) rs117353193 TCN2 (Pcombined=6.15×10-13; 1.43), associated high-serum cases. Additionally, another (rs2107595 HDAC9; Pcombined=1.49×10-29; 1.64) implicated large-vessel disease. Tissue enrichment that highly expressed immune system (false rate, <0.05).This identifies several susceptibility for MMD. The metabolism gene expression suggest therapeutic interventions targeting pathways may be effective approaches treatment.