1

Introduction

Myopia is a form of refractive error in which parallel light from distant objects is focused in front of the retina in a nonaccomodative eye. It is the most common ocular disorder with a prevalence of approximately 50 % of the world’s population. The refractive errors in myopia can be effectively corrected by optical and laser treatments in most people, but the risk of subsequent sight-threatening conditions such as glaucoma, macular degeneration and retinal detachment is increased with the degree of myopia, especially for high myopia.

The etiological heterogeneity of myopia can be attributed to the interplays among environmental and genetic influences. Children are subject to less environmental influences with shorter durations than adults. The myopia development in childhood is driven more by genetic predispositions. Genome-wide association studies (GWAS) and subsequent metaanalyses have identified more than 400 loci associated with myopia and refraction. The majority of the study populations are adults. Whether these significant effects of the single nucleotide polymorphisms (SNPs) still apply to children have to be investigated. In this review, we summarized those genetic variants identified in adult cohorts by GWAS that have been replicated in children and adolescent cohorts. We also compared the effect size between children and adults, aiming for a better understanding of the underlying genetic mechanisms of myopia between adults and children and possible myopia genetic markers for different age groups.

2

Genetic loci in myopia

2.1

Genetic loci in children myopia

Myopia can be classified by a variety of ways based on the presumed etiology, age of onset, progression pattern, amount of myopia and structural complications. However, there are interactions among the different conditions. For example, syndromic myopia often manifests as a high degree of myopia accompanied by severe ocular complications, which can be caused by gene mutations with high penetration and manifests at birth or in early childhood. However, syndromic myopia typically involves rare genetic syndromes and distinct clinical features that are distinct from the more common complex myopia and its genetic causes can be found elsewhere. In this review, we focus on common myopia, which are complex in etiology and manifestation. It can be influenced by multiple genetic variants, each contributing to a small effect, as reflected in GWAS findings. Additionally, common myopia is significantly modified by environmental factors, especially lifestyle in near work and outdoor time, highlighting the interplays among genetic predispositions and external influences in its development. Replicated SNPs and phenotypes have been investigated ( Table 1 ). There are reported comparisons of effect size between adults, principally from GWAS, and children, principally from candidate SNP studies ( Table 2 ).

Table 1

Replication loci in children cohorts.

Loci	Ethnicities	N	Age (year)	Phenotype
Myopia and progression
GJD2	Southern Han Chinese	1043	6–8	SE progression, AL elongation
	European	5200	7.5–15	Later-onset myopia
KCNQ5	Southern Han Chinese	1043	6–8	SE progression, AL elongation
	European	5200	7.5–15	Early and later-onset myopia
	European and Asian	5599	6.6–20	Cross-sectional myopia
ZFHX1B	Southern Han Chinese	1043	6–8	SE progression
A2BP1	European	5200	7.5–15	Later-onset myopia
	European and Asian	5599	6.6–20	Cross-sectional myopia
ZIC2	European	5200	7.5–15	Early and later-onset myopia
	European and Asian	5599	6.6–20	Cross-sectional myopia
TOX	European	5200	7.5–15	Early and later-onset myopia
	European and Asian	5599	6.6–20	Cross-sectional myopia
KCNMA1	European	5200	7.5–15	Later-onset myopia
LAMA2	European	5200	7.5	Early-onset myopia
SHISA6	European	5200	7.5–15	Early and later-onset myopia
PRSS56	European	5200	7.5–15	Early and later-onset myopia
CD55	European	5200	7.5–15	Later-onset myopia
CHRNG	European	5200	7.5	Early-onset myopia
CHD7	European	5200	7.5–15	Later-onset myopia
RORB	European	5200	7.5–15	Later-onset myopia
CYP26A1	European	5200	7.5	Early-onset myopia
BMP4	European	5200	7.5	Early-onset myopia
RASGRF1	Southern Han Chinese	426	7.28	Myopic shift
PTPN5	Southern Han Chinese	426	7.28	Myopic shift, AL elongation, LT increasing
PDGFRA	Southern Han Chinese	426	7.28	LT increasing
AREG	Southern Han Chinese	469	6.33	AL elongation
PDE10A	Southern Han Chinese	469	6.33	CC increasing
TGFBR1	Southern Han Chinese	448	7.29	Myopic shift, AL elongation, AL/CR increasing
TGFB2-AS1	Southern Han Chinese	448	7.29	Myopia onset
Severities and endophenotypes
GJD2	Southern Han Chinese	3300	5–10	Mild myopia, SE, AL, AL/CR
	European and Asian	5490	< 10	AL/CR
		5000	10–25
		16274	> 25
KCNQ5	Southern Han Chinese	3300	5–10	SE, AL, AL/CR
	European and Asian	5000	10–25	AL/CR
ZFHX1B	Southern Han Chinese	3300	5–10	SE
ZC3H11B	Southern Han Chinese	3300	5–10	Moderate and high myopia, SE, AL, AL/CR
SNTB1	Southern Han Chinese	3300	5–10	AL, CR
BICC1	Southern Han Chinese	3300	5–10	Moderate and high myopia, SE, CR
	European and Asian	5490	< 10	AL/CR
		5000	10–25	AL/CR
		16274	> 25	AL/CR
PRSS56	European and Asian	5490	< 10	AL/CR
		5000	10–25
		16274	> 25
KCNMA1	European and Asian	5490	< 10	AL/CR
ZIC2	European and Asian	5490	< 10	AL/CR
CHRNG	European and Asian	5490	< 10	AL/CR
BMP2	European and Asian	5000	10–25	AL/CR
A2BP1	European and Asian	5000	10–25	AL/CR
CACNA1D	European and Asian	5000	10–25	AL/CR
RSPO1	Southern Han Chinese	2883	7.55	AL
WNT7B	Southern Han Chinese	2883	7.55	AL, CC, CCT
ZNRF3	Southern Han Chinese	2883	7.55	CC
RASGRF1	Southern Han Chinese	426	7.28	SE and AL
PTPN5	Southern Han Chinese	426	7.28	CCT
PDGFRA	Southern Han Chinese	426	7.28	LT, ACD
Opposite direction of effects
BMP2	European, Asian, African	10490	< 10, 10–25	AL/CR
BMP4	European, Asian, African	10490	< 10, 10–25	AL/CR
MYO1D	European, Asian, African	10490	< 10, 10–25	AL/CR
PTPRR	European, Asian, African	10490	< 10, 10–25	AL/CR
IGF1	Chinese	654	8.06	Myopia

 

ACD, anterior chanmber depth; AL, axial length; AL/CR, the ratio of AL to corneal radius; CC, corneal curvature; CCT, central corneal thickness; LT, lense thickness; SE, spherical equivalent.

Table 2

Effects of SE and AL between adults and children.

Gene	SNP	Phentypes	A1/A2	MAF	Beta	Ethnicity		MAF	Beta	Ethnicity
				Adult cohorts from GWAS				Children cohorts from candidate studies
A2BP1	rs17648524	SE	C/G	0.36	−0.116	European		0.33	−0.001	European
BICC1	rs7084402	SE	G/A	0.48	−0.111	European		0.45	−0.08	Southern Han Chinese
BMP2	rs235770	SE	T/C	0.39	−0.088	European		0.3	−0.04	Southern Han Chinese
CACNA1D	rs14165	SE	A/G	0.32	0.095	European		0.3	0.04	European
CD55	rs1652333	SE	G/A	0.32	−0.115	European		0.32	−0.002	European
CHD7	rs4237036	SE	C/T	0.35	0.097	European		0.34	0.02 *	European
CHRNG	rs1881492	SE	T/G	0.22	−0.145	European		0.23	−0.058	European
CYP26A1	rs10882165	SE	T/A	0.42	−0.111	European		0.4	−0.035	European
GJD2	rs524952	SE	A/T	0.48	−0.154	European		0.56	0.12 *	Southern Han Chinese
								0.46	−0.018	European
	rs11073058	AL	T/G	0.43	0.07	European		0.42	0.044	Southern Han Chinese
GRIA4	rs11601239	SE	C/G	0.46	−0.092	European		NA	−0.084	Southern Han Chinese
KCNQ5	rs7744813	SE	C/A	0.112	0.019	European		0.2	0.24	Southern Han Chinese
								0.41	0.048	European
LAMA2	rs12205363	SE	C/T	0.1	0.228	European		0.08	0.097 *	European
PRSS56	rs1656404	SE	A/G	0.21	−0.151	European		0.21	−0.066	European
RDH5	rs3138144	SE	C/G	0.48	0.113	European		NA	0.061	Southern Han Chinese
RORB	rs7042950	SE	G/A	0.24	−0.113	European		0.22	0.018	European
RSPO1	rs12144790	AL	T/C	0.43	0.06	European		0.385	0.062	Southern Han Chinese
SHISA6	rs2969180	SE	A/G	0.36	−0.101	European		0.35	−0.039	European
TOX	rs7837791	SE	T/G	0.49	0.106	European		0.47	0.045 *	European
WNT7B	rs10453441	AL	A/G	0.306	0.12	European		0.343	0.103	Southern Han Chinese
ZC3H11B	rs4373767	AL	C/T	0.3	−0.16	European		0.293	−0.053	Southern Han Chinese
ZIC2	rs8000973	SE	T/C	0.47	0.089	European		0.48	0.042 *	European
ZMAT4	rs7829127	SE	G/A	0.25	0.116	European		NA	0.233	Southern Han Chinese
ZNRF3	rs12321	AL	C/G	0.44	−0.05	European		0.426	−0.027	Southern Han Chinese

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