{"title":"近视性黄斑新生血管的全基因组 Meta 分析发现了一个新的易感基因位点，并揭示了与年龄相关性黄斑变性的共同遗传易感性。","authors":"Kazuya Morino, Masahiro Miyake, Masao Nagasaki, Takahisa Kawaguchi, Shogo Numa, Yuki Mori, Shota Yasukura, Masahiro Akada, Shin-Ya Nakao, Ai Nakata, Hiroki Hashimoto, Ryoko Otokozawa, Koju Kamoi, Hiroyuki Takahashi, Yasuharu Tabara, Fumihiko Matsuda, Kyoko Ohno-Matsui, Akitaka Tsujikawa","doi":"10.1016/j.oret.2024.09.016","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia.</p><p><strong>Design: </strong>A genome-wide association study (GWAS) meta-analysis (meta-GWAS).</p><p><strong>Participants: </strong>We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV.</p><p><strong>Methods: </strong>We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci.</p><p><strong>Main outcome measures: </strong>The association between SNPs and mMNV in patients with high myopia.</p><p><strong>Results: </strong>The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]<sub>meta</sub> = 0.62, P<sub>meta</sub> = 4.63 × 10<sup>-8</sup>, I<sup>2</sup> = 0.00), which was consistently associated with mMNV in all datasets (OR<sub>ASA</sub> = 0.59, P<sub>ASA</sub> = 1.71 × 10<sup>-4</sup>; OR<sub>610K</sub> = 0.63, P<sub>610K</sub> = 5.53 × 10<sup>-4</sup>; OR<sub>WGS</sub> = 0.66, P<sub>WGS</sub> = 4.38 × 10<sup>-2</sup>). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (OR<sub>meta</sub> = 0.52, P<sub>meta</sub> = 1.55 × 10<sup>-5</sup>), while rs61871745 near ARMS2 showed a marginal association (OR<sub>meta</sub> = 1.25, P<sub>meta</sub> =7.79 × 10<sup>-3</sup>).</p><p><strong>Conclusions: </strong>Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.</p>","PeriodicalId":19501,"journal":{"name":"Ophthalmology. Retina","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-related Macular Degeneration.\",\"authors\":\"Kazuya Morino, Masahiro Miyake, Masao Nagasaki, Takahisa Kawaguchi, Shogo Numa, Yuki Mori, Shota Yasukura, Masahiro Akada, Shin-Ya Nakao, Ai Nakata, Hiroki Hashimoto, Ryoko Otokozawa, Koju Kamoi, Hiroyuki Takahashi, Yasuharu Tabara, Fumihiko Matsuda, Kyoko Ohno-Matsui, Akitaka Tsujikawa\",\"doi\":\"10.1016/j.oret.2024.09.016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia.</p><p><strong>Design: </strong>A genome-wide association study (GWAS) meta-analysis (meta-GWAS).</p><p><strong>Participants: </strong>We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV.</p><p><strong>Methods: </strong>We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci.</p><p><strong>Main outcome measures: </strong>The association between SNPs and mMNV in patients with high myopia.</p><p><strong>Results: </strong>The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]<sub>meta</sub> = 0.62, P<sub>meta</sub> = 4.63 × 10<sup>-8</sup>, I<sup>2</sup> = 0.00), which was consistently associated with mMNV in all datasets (OR<sub>ASA</sub> = 0.59, P<sub>ASA</sub> = 1.71 × 10<sup>-4</sup>; OR<sub>610K</sub> = 0.63, P<sub>610K</sub> = 5.53 × 10<sup>-4</sup>; OR<sub>WGS</sub> = 0.66, P<sub>WGS</sub> = 4.38 × 10<sup>-2</sup>). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (OR<sub>meta</sub> = 0.52, P<sub>meta</sub> = 1.55 × 10<sup>-5</sup>), while rs61871745 near ARMS2 showed a marginal association (OR<sub>meta</sub> = 1.25, P<sub>meta</sub> =7.79 × 10<sup>-3</sup>).</p><p><strong>Conclusions: </strong>Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.</p>\",\"PeriodicalId\":19501,\"journal\":{\"name\":\"Ophthalmology. Retina\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ophthalmology. Retina\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.oret.2024.09.016\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ophthalmology. Retina","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.oret.2024.09.016","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-related Macular Degeneration.
Purpose: To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia.
Design: A genome-wide association study (GWAS) meta-analysis (meta-GWAS).
Participants: We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV.
Methods: We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci.
Main outcome measures: The association between SNPs and mMNV in patients with high myopia.
Results: The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]meta = 0.62, Pmeta = 4.63 × 10-8, I2 = 0.00), which was consistently associated with mMNV in all datasets (ORASA = 0.59, PASA = 1.71 × 10-4; OR610K = 0.63, P610K = 5.53 × 10-4; ORWGS = 0.66, PWGS = 4.38 × 10-2). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORmeta = 0.52, Pmeta = 1.55 × 10-5), while rs61871745 near ARMS2 showed a marginal association (ORmeta = 1.25, Pmeta =7.79 × 10-3).
Conclusions: Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.
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