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Genome-wide association study identifies novel susceptibilities to adult moyamoya disease

Journal of Human Genetics volume 68, pages 713–720 (2023)Cite this article

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Abstract

Genome-wide association study has limited to discover single-nucleotide polymorphisms (SNPs) in several ethnicities. Here, we investigated an initial GWAS to identify genetic modifiers predicting with adult moyamoya disease (MMD) in Koreans. GWAS was performed in 216 patients with MMD and 296 controls using the large-scale Asian-specific Axiom Precision Medicine Research Array. A subsequent fine-mapping analysis was conducted to assess the causal variants associated with adult MMD. A total of 489,966 out of 802,688 SNPs were subjected to quality control analysis. Twenty-one SNPs reached a genome-wide significance threshold (p = 5 × 10−8) after pruning linkage disequilibrium (r2 < 0.8) and mis-clustered SNPs. Among these variants, the 17q25.3 region including TBC1D16, CCDC40, GAA, RNF213, and ENDOV genes was broadly associated with MMD (p = 3.1 × 10−20 to 4.2 × 10−8). Mutations in RNF213 including rs8082521 (Q1133K), rs10782008 (V1195M), rs9913636 (E1272Q), rs8074015 (D1331G), and rs9674961 (S2334N) showed a genome-wide significance (1.9 × 10−8 < p < 4.3 × 10−12) and were also replicated in the East-Asian populations. In subsequent analysis, RNF213 mutations were validated in a fine-mapping outcome (log10BF > 7). Most of the loci associated with MMD including 17q25.3 regions were detected with a statistical power greater than 80%. This study identifies several novel and known variations predicting adult MMD in Koreans. These findings may good biomarkers to evaluate MMD susceptibility and its clinical outcomes.

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Acknowledgements

This research was supported by a grant of the Seoul National University Hospital (grant number: 0320180090) and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR21C0198). In addition, all authors thank all members manufacturing “The First Korean Stroke Genetics Association Research (The FirstKSGAR, https://1ksgh.org/)” consortium, who correct biospecimen and clinical datasets.

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  1. These authors contributed equally: Jin Pyeong Jeon, Eun Pyo Hong.

Authors and Affiliations

  1. Department of Neurosurgery, Hallym University College of Medicine, Chuncheon, Republic of Korea

    Jin Pyeong Jeon

  2. Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Republic of Korea

    Jin Pyeong Jeon, Eun Pyo Hong, Bong Jun Kim & Dong Hyuk Youn

  3. Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Republic of Korea

    Eun Jin Ha, Hee Chang Lee, Kang Min Kim, Sung Ho Lee, Won-Sang Cho, Hyun-Seung Kang & Jeong Eun Kim

  4. Department of Genomic Medicine, Center for Precision Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Sungyoung Lee

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Contributions

JEK designed and managed this study. All of analysis and result interpretation were equally done by JPJ and EPH Sample preparation and data collection were done by EJH, BJK, DHY, SL, HCL, KMK, SHL, WSC, and HSK. Drafting and reviewing of manuscript were done by JPJ, EPH, EJH, BJK, DHY, SL, HCL, KMK, SHL, WSC, HSK, and JEK.

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Correspondence to Jeong Eun Kim.

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Jeon, J.P., Hong, E.P., Ha, E.J. et al. Genome-wide association study identifies novel susceptibilities to adult moyamoya disease. J Hum Genet 68, 713–720 (2023). https://doi.org/10.1038/s10038-023-01167-9

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