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

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

doi:10.1161/STROKEAHA.117.017430

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

Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.

Authors

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

Affiliations

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.

PMID: 29273593
DOI: 10.1161/STROKEAHA.117.017430

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 (P_combined=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 (P_combined=2.49×10^-19; odds ratio, 0.65) and rs117353193 in TCN2 (P_combined=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; P_combined=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.

Keywords: genome-wide association study; homocysteine; humans; moyamoya disease; odds ratio.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Histone Deacetylases / genetics
Humans
Methylenetetrahydrofolate Reductase (NADPH2) / genetics
Moyamoya Disease / genetics*
Polymorphism, Single Nucleotide*
Repressor Proteins / genetics
Ubiquitin-Protein Ligases / genetics

Substances

Repressor Proteins
MTHFR protein, human
Methylenetetrahydrofolate Reductase (NADPH2)
RNF213 protein, human
Ubiquitin-Protein Ligases
HDAC9 protein, human
Histone Deacetylases
Adenosine Triphosphatases