Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia
NATURE GENETICS
Authors: Verhoeven, Virginie J. M.; Hysi, Pirro G.; Wojciechowski, Robert; Fan, Qiao; Guggenheim, Jeremy A.; Hoehn, Rene; MacGregor, Stuart; Hewitt, Alex W.; Nag, Abhishek; Cheng, Ching-Yu; Yonova-Doing, Ekaterina; Zhou, Xin; Ikram, M. Kamran; Buitendijk, Gabrielle H. S.; McMahon, George; Kemp, John P.; St Pourcain, Beate; Simpson, Claire L.; Makela, Karl-Matti; Lehtimaki, Terho; Kahonen, Mika; Paterson, Andrew D.; Hosseini, S. Mohsen; Wong, Hoi Suen; Xu, Liang; Jonas, Jost B.; Parssinen, Olavi; Wedenoja, Juho; Yip, Shea Ping; Ho, Daniel W. H.; Pang, Chi Pui; Chen, Li Jia; Burdon, Kathryn P.; Craig, Jamie E.; Klein, Barbara E. K.; Klein, Ronald; Haller, Toomas; Metspalu, Andres; Khor, Chiea-Chuen; Tai, E-Shyong; Aung, Tin; Vithana, Eranga; Tay, Wan-Ting; Barathi, Veluchamy A.; Chen, Peng; Li, Ruoying; Liao, Jiemin; Zheng, Yingfeng; Ong, Rick T.; Doering, Angela; Evans, David M.; Timpson, Nicholas J.; Verkerk, Annemieke J. M. H.; Meitinger, Thomas; Raitakari, Olli; Hawthorne, Felicia; Spector, Tim D.; Karssen, Lennart C.; Pirastu, Mario; Murgia, Federico; Ang, Wei; Mishra, Aniket; Montgomery, Grant W.; Pennell, Craig E.; Cumberland, Phillippa M.; Cotlarciuc, Ioana; Mitchell, Paul; Wang, Jie Jin; Schache, Maria; Janmahasathian, Sarayut; Igo, Robert P., Jr.; Lass, Jonathan H.; Chew, Emily; Iyengar, Sudha K.; Gorgels, Theo G. M. F.; Rudan, Igor; Hayward, Caroline; Wright, Alan F.; Polasek, Ozren; Vatavuk, Zoran; Wilson, James F.; Fleck, Brian; Zeller, Tanja; Mirshahi, Alireza; Mueller, Christian; Uitterlinden, Andre G.; Rivadeneira, Fernando; Vingerling, Johannes R.; Hofman, Albert; Oostra, Ben A.; Amin, Najaf; Bergen, Arthur A. B.; Teo, Yik-Ying; Rahi, Jugnoo S.; Vitart, Veronique; Williams, Cathy; Baird, Paul N.; Wong, Tien-Yin; Oexle, Konrad; Pfeiffer, Norbert; Mackey, David A.; Young, Terri L.; van Duijn, Cornelia M.; Saw, Seang-Mei; Bailey-Wilson, Joan E.; Stambolian, Dwight; Klaver, Caroline C.; Hammond, Christopher J.
Abstract
Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
Comprehensive Replication of the Relationship Between Myopia-Related Genes and Refractive Errors in a Large Japanese Cohort
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Authors: Yoshikawa, Munemitsu; Yamashiro, Kenji; Miyake, Masahiro; Oishi, Maho; Akagi-Kurashige, Yumiko; Kumagai, Kyoko; Nakata, Isao; Nakanishi, Hideo; Oishi, Akio; Gotoh, Norimoto; Yamada, Ryo; Matsuda, Fumihiko; Yoshimura, Nagahisa
Abstract
PURPOSE. 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.
COA
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