title: Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort.
abstract: OBJECTIVE
  We investigated the association between refractive error in a Japanese population and myopia-related genes identified in two recent large-scale genome-wide association studies.
  
  
  METHODS
  Single-nucleotide polymorphisms (SNPs) in 51 genes that were reported by the Consortium for Refractive Error and Myopia and/or the 23andMe database were genotyped in 3712 healthy Japanese volunteers from the Nagahama Study using HumanHap610K Quad, HumanOmni2.5M, and/or HumanExome Arrays. To evaluate the association between refractive error and recently identified myopia-related genes, we used three approaches to perform quantitative trait locus analyses of mean refractive error in both eyes of the participants: per-SNP, gene-based top-SNP, and gene-based all-SNP analyses. Association plots of successfully replicated genes also were investigated.
  
  
  RESULTS
  In our per-SNP analysis, eight myopia gene associations were replicated successfully: GJD2, RASGRF1, BICC1, KCNQ5, CD55, CYP26A1, LRRC4C, and B4GALNT2.Seven additional gene associations were replicated in our gene-based analyses: GRIA4, BMP2, QKI, BMP4, SFRP1, SH3GL2, and EHBP1L1. The signal strength of the reported SNPs and their tagging SNPs increased after considering different linkage disequilibrium patterns across ethnicities. Although two previous studies suggested strong associations between PRSS56, LAMA2, TOX, and RDH5 and myopia, we could not replicate these results.
  
  
  CONCLUSIONS
  Our results confirmed the significance of the myopia-related genes reported previously and suggested that gene-based replication analyses are more effective than per-SNP analyses. Our comparison with two previous studies suggested that BMP3 SNPs cause myopia primarily in Caucasian populations, while they may exhibit protective effects in Asian populations.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Munemitsu
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Oishi
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Akagi-Kurashige
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nakata
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Oishi
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Norimoto
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
mesh_terms: D000328:Adult; D000368:Aged; D004247:DNA / Q000235:genetics*; D004261:DNA Replication; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009216:Myopia / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011446:Prospective Studies; D012030:Refractive Errors / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D012424:Rural Population
chemical_list: D005136:Eye Proteins; D004247:DNA
keywords: Japanese; gene-based replication; genome-wide association study; myopia; refractive error