Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia.
Severe myopia (defined as spherical equivalent < -6.0 D) is a predominant problem in Asian countries, resulting in substantial morbidity. We performed a meta-analysis of four genome-wide association studies (GWAS), all of East Asian descent totaling 1603 cases and 3427 controls. Two single nucleotide polymorphisms (SNPs) (rs13382811 from ZFHX1B [encoding for ZEB2] and rs6469937 from SNTB1) showed highly suggestive evidence of association with disease (P < 1 × 10(-7)) and were brought forward for replication analysis in a further 1241 severe myopia cases and 3559 controls from a further three independent sample collections. Significant evidence of replication was observed, and both SNP markers surpassed the formal threshold for genome-wide significance upon meta-analysis of both discovery and replication stages (P = 5.79 × 10(-10), per-allele odds ratio (OR) = 1.26 for rs13382811 and P = 2.01 × 10(-9), per-allele OR = 0.79 for rs6469937). The observation at SNTB1 is confirmatory of a very recent GWAS on severe myopia. Both genes were expressed in the human retina, sclera, as well as the retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia.
Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
Chiea Chuen
CC
Khor
Masahiro
M
Miyake
Li Jia
LJ
Chen
Yi
Y
Shi
Veluchamy A
VA
Barathi
Fan
F
Qiao
Isao
I
Nakata
Kenji
K
Yamashiro
Xin
X
Zhou
Pancy O S
PO
Tam
Ching-Yu
CY
Cheng
E Shyong
ES
Tai
Eranga N
EN
Vithana
Tin
T
Aung
Yik-Ying
YY
Teo
Tien-Yin
TY
Wong
Muka
M
Moriyama
Kyoko
K
Ohno-Matsui
Manabu
M
Mochizuki
Fumihiko
F
Matsuda
Rita Y Y
RY
Yong
Eric P H
EP
Yap
Zhenglin
Z
Yang
Chi Pui
CP
Pang
Seang-Mei
SM
Saw
Nagahisa
N
Yoshimura
D000483:Alleles; D000818:Animals; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009216:Myopia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012590:Sclera / Q000378:metabolism / Q000473:pathology; D000074165:Zinc Finger E-box Binding Homeobox 2
D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2