Lian Duan1, Ling Wei1, Yanghua Tian1, Zhengshan Zhang1, Panpan Hu1, Qiang Wei1, Sugang Liu1, Jun Zhang1, Yuyang Wang1, Desheng Li1, Weizhong Yang1, Rui Zong1, Peng Xian1, Cong Han1, Xiangyang Bao1, Feng Zhao1, Jie Feng1, Wei Liu1, Wuchun Cao1, Guoping Zhou1, Chunyan Zhu1, Fengqiong Yu1, Weimin Yang1, Yu Meng1, Jingye Wang1, Xianwen Chen1, Yu Wang1, Bing Shen1, Bing Zhao1, Jinghai Wan1, Fengyu Zhang1, Gang Zhao1, Aimin Xu1, Xuejun Zhang1, Jianjun Liu1, Xianbo Zuo1, Kai Wang2. 1. From the Department of Neurosurgery, 307 Hospital, PLA Center for Cerebral Vascular Disease, Clinical Colleague of Anhui Medical University, Beijing, China (L.D., Z.Z., S.L., D.L., W.Y., R.Z., P.X., C.H., X.B., F.Z., J.F.); Department of Neurology (L.W., Y.T., P.H., Q.W., J.Z., W.Y., Y.M., J.W., X.C., Y.W., K.W.) and Department of Dermatology (F.Z., X. Zhang, X. Zuo), First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Neurosurgery, Second Affiliated Hospital of Anhui Medical University, Hefei, China (Y.W., B.Z., J.W.); Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, China (W.L., W.C., J.L.); Department of Neurosurgery, Nanyang City Center Hospital, Henan, China (G.Z.); Department of Medical Psychology (C.Z., F.Y.) and Department of Physiology, School of Basic Medicine (B.S.), Anhui Medical University, Hefei, China); State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China (F.Z., X. Zhang, X. Zuo); Department of Neurology, Xijing Hospital, Fourth Military Medical University, China (G.Z.); Department of Medicine (A.X.), Department of Pharmacology and Pharmacy (A.X.), and State Key Laboratory of Pharmaceutical Biotechnology (A.X.), Hong Kong University, China; Department of Human Genetics, Genome Institute of Singapore, A*STAR (J.L.); and Anhui Collaborative Innovation Center of Neuropsychiatric Disorder and Mental Health, Hefei, China (K.W.). 2. From the Department of Neurosurgery, 307 Hospital, PLA Center for Cerebral Vascular Disease, Clinical Colleague of Anhui Medical University, Beijing, China (L.D., Z.Z., S.L., D.L., W.Y., R.Z., P.X., C.H., X.B., F.Z., J.F.); Department of Neurology (L.W., Y.T., P.H., Q.W., J.Z., W.Y., Y.M., J.W., X.C., Y.W., K.W.) and Department of Dermatology (F.Z., X. Zhang, X. Zuo), First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Neurosurgery, Second Affiliated Hospital of Anhui Medical University, Hefei, China (Y.W., B.Z., J.W.); Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, China (W.L., W.C., J.L.); Department of Neurosurgery, Nanyang City Center Hospital, Henan, China (G.Z.); Department of Medical Psychology (C.Z., F.Y.) and Department of Physiology, School of Basic Medicine (B.S.), Anhui Medical University, Hefei, China); State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China (F.Z., X. Zhang, X. Zuo); Department of Neurology, Xijing Hospital, Fourth Military Medical University, China (G.Z.); Department of Medicine (A.X.), Department of Pharmacology and Pharmacy (A.X.), and State Key Laboratory of Pharmaceutical Biotechnology (A.X.), Hong Kong University, China; Department of Human Genetics, Genome Institute of Singapore, A*STAR (J.L.); and Anhui Collaborative Innovation Center of Neuropsychiatric Disorder and Mental Health, Hefei, China (K.W.). wangkai1964@126.com 28080806@qq.com.
Abstract
BACKGROUND AND PURPOSE: 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 is well recognized, the genetic basis of MMD remains poorly understood. METHODS: A 2-stage genome-wide association study was conducted involving 1492 cases and 5084 controls. In the discovery stage, logistic regression was used to test associations, and imputation was conducted based on genotyped single-nucleotide polymorphisms (SNPs). In the validation stage, the top significant SNPs were again genotyped in an independent cohort. Fixed-effects inverse variance-weighted meta-analysis was used in the combined discovery and validation samples. Furthermore, association analysis was conducted in subgroups using patient clinical data. RESULTS: The study identified 10 novel risk loci with genome-wide significance (P<5×10-8) and confirmed a previously reported locus on 17q25. No significant SNP showed evidence of heterogeneity between the 2 stages. Cumulatively, these SNPs explained 14.76% of disease risk variance-a substantial proportion of the 39.02% of risk variance explained by all genome-wide genotyped SNPs. One SNP, rs9916351 in RNF213 (Pcombined=4.57×10-54; odds ratio, 1.96), showed a stronger genetic effect on early-onset than late-onset MMD (P=0.003). Two novel SNPs in genes regulating homocysteine metabolism, rs9651118 in MTHFR (Pcombined=2.49×10-19; odds ratio, 0.65) and rs117353193 in TCN2 (Pcombined=6.15×10-13; odds ratio, 1.43), were associated with high-serum homocysteine in MMD cases. Additionally, another SNP associated with MMD (rs2107595 in HDAC9; Pcombined=1.49×10-29; odds ratio, 1.64) was previously implicated in large-vessel disease. Tissue enrichment analysis showed that the genes of associated loci were highly expressed in the immune system (false discovery rate, <0.05). CONCLUSIONS: This study identifies several novel susceptibility genes for MMD. The association with homocysteine metabolism and the immune system enrichment of susceptibility gene expression suggest that therapeutic interventions targeting these pathways may be effective approaches for MMD treatment.
BACKGROUND AND PURPOSE: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 is well recognized, the genetic basis of MMD remains poorly understood. METHODS: A 2-stage genome-wide association study was conducted involving 1492 cases and 5084 controls. In the discovery stage, logistic regression was used to test associations, and imputation was conducted based on genotyped single-nucleotide polymorphisms (SNPs). In the validation stage, the top significant SNPs were again genotyped in an independent cohort. Fixed-effects inverse variance-weighted meta-analysis was used in the combined discovery and validation samples. Furthermore, association analysis was conducted in subgroups using patient clinical data. RESULTS: The study identified 10 novel risk loci with genome-wide significance (P<5×10-8) and confirmed a previously reported locus on 17q25. No significant SNP showed evidence of heterogeneity between the 2 stages. Cumulatively, these SNPs explained 14.76% of disease risk variance-a substantial proportion of the 39.02% of risk variance explained by all genome-wide genotyped SNPs. One SNP, rs9916351 in RNF213 (Pcombined=4.57×10-54; odds ratio, 1.96), showed a stronger genetic effect on early-onset than late-onset MMD (P=0.003). Two novel SNPs in genes regulating homocysteine metabolism, rs9651118 in MTHFR (Pcombined=2.49×10-19; odds ratio, 0.65) and rs117353193 in TCN2 (Pcombined=6.15×10-13; odds ratio, 1.43), were associated with high-serum homocysteine in MMD cases. Additionally, another SNP associated with MMD (rs2107595 in HDAC9; Pcombined=1.49×10-29; odds ratio, 1.64) was previously implicated in large-vessel disease. Tissue enrichment analysis showed that the genes of associated loci were highly expressed in the immune system (false discovery rate, <0.05). CONCLUSIONS: This study identifies several novel susceptibility genes for MMD. The association with homocysteine metabolism and the immune system enrichment of susceptibility gene expression suggest that therapeutic interventions targeting these pathways may be effective approaches for MMD treatment.