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The Genetics of Myopia

Open Access
Chapter

Abstract

Myopia is the most common eye condition worldwide and its prevalence is increasing. While changes in environment, such as time spent outdoors, have driven myopia rates, within populations myopia is highly heritable. Genes are estimated to explain up to 80% of the variance in refractive error. Initial attempts to identify myopia genes relied on family studies using linkage analysis or candidate gene approaches with limited progress. More genome-wide association study (GWAS) approaches have taken over, ultimately resulting in the identification of hundreds of genes for refractive error and myopia, providing new insights into its molecular machinery. These studies showed myopia is a complex trait, with many genetic variants of small effect influencing retinal signaling, eye growth and the normal process of emmetropization. The genetic architecture and its molecular mechanisms are still to be clarified and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice.

Keywords

Myopia Refractive error Genetics Linkage Candidate genes GWAS GxE interactions Mendelian randomization Pathway analysis Whole exome sequencing Whole genome sequencing Epigenetics 

Key Points

  • While the recent global rise of myopia prevalence is primarily attributable to environmental changes, within populations inherited factors play a large role in explaining why some individuals are affected by myopia while others are not.

  • Early efforts to identify the specific genes underlying the heritability of refractive error used linkage and candidate gene designs to identify up to 50 loci and genes, although most remain unconfirmed.

  • As the sample size in genome-wide association studies (GWAS) has increased, the number of implicated loci has risen steadily, with 161 variants reported in the latest meta-analysis.

  • Interrogation of loci uncovered by GWAS offers insight into the molecular basis of myopia—for example, pathway analysis implicates the light induced retina-to-sclera signaling pathway in myopia development.

  • Although many loci have been uncovered by GWAS, statistical modelling shows there are many more genes to find—identifying these will further illuminate the molecular pathways leading to myopia and open up new avenues for intervention.

5.1 Introduction

This chapter addresses the scientific exploration of the genetic architecture of myopia. Myopia is the most common eye condition worldwide and its prevalence is increasing. Changes in environmental conditions where time spent outdoors has reduced relative to previous generations are the main hypothesized culprit. Despite these environmental trends, within populations, myopia is highly heritable; genes explain up to 80% of the variance in refractive error. Initial attempts to identify myopia genes relied on family studies using linkage analysis or candidate gene approaches with limited progress. For the last decade, genome-wide association study (GWAS) approaches have predominated, ultimately resulting in the identification of hundreds of genes for refractive error and myopia, providing new insights into its molecular machinery. Thanks to these studies, it was revealed that myopia is a complex trait, with many genetic variants of small effect influencing retinal signaling, eye growth and the normal process of emmetropization. However, the genetic architecture and its molecular mechanisms are still to be clarified and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice.

Some sections of this report follow the framework described in a recent International Myopia Institute Genetics report by Tedja et al. [1]

5.2 Heritability

The tendency for myopia to run in families has long been noted, suggesting genetic factors play a role in determining risk [2]. While family studies show familial aggregation, twin studies are required to reliably separate the effects of genes and familial environment [3, 4, 5, 6]. Benchmarking of the relative contribution of genetics and environment is done by computation of heritability, the proportion of the total trait variance (here, spherical equivalent) due to additive genetic factors. Since the contributions of genes and environment can vary across human populations, heritabilities are population and even time specific [7, 8]. The influence of environmental variance is well illustrated in the case of the heritability study in Alaskan Eskimos, where the rapid introduction of the American school system dramatically increased the contribution of the environment. As a result heritability estimates, computed based on families where the parents are less educated relative to their offspring, were very low at this time (10%) [7].

Across most human populations, environment is fairly constant and the estimates of spherical equivalent heritability are usually high (~80%) [9, 10, 11]. Although the aggregate contribution of genetic factors to variation in refractive error is high, initial studies were unable to determine the genetic architecture of myopia—that is, is myopia caused by rare mutations of large effect? Or is most variation driven by common variants, each with individually small effect on risk? With the advent of genotyping arrays, it became possible to estimate the aggregate effect of all common variants, with “array heritability” estimates of 35% from the ALSPAC study. Such estimates place a lower bound on the proportion of the heritability that is attributable to genetic variants which are common in the population. The remaining 45% (80%–35%) is likely attributable to rare genetic variants, to variants not covered by genotyping arrays or to non-additive genetic effects.

5.3 Syndromic Myopia

Syndromic myopia is generally monogenic and can occur within a wide spectrum of clinical presentations. This type of myopia is usually accompanied by other systemic or ocular disorders. Table 5.1 summarizes all syndromic and ocular conditions that present with myopia [12]. We are able to learn about myopia development by investigating these syndromes. For instance, several types of heritable syndromes result in extreme axial elongation, due to abnormalities in the development of connective tissue (i.e. Marfan syndrome, OMIM #154700; Stickler syndrome, OMIM #,108300 #604841, #614134, #614284 and Ehlers–Danlos syndrome, OMIM #225400, #601776). Similarly, inherited retinal dystrophies lead to myopia due to defects in photoreceptors, for instance, in X-linked retinitis pigmentosa (mutations in RPGR-gene) and congenital stationary night blindness [13].
Table 5.1

Overview of syndromic forms of myopia

Syndrome

Gene and inheritance pattern

Ocular phenotype other than myopia

(A) Syndromes associated with myopia and associated ocular phenotype

Acromelic frontonasal dysostosis

ZSWIM6 (AD)

Telecanthus, ptosis (some patients), corneal dermoid cyst (rare), glaucoma (rare), segmental optic nerve hypoplasia (rare), persistent primary vitreous (rare)

Alagille syndrome

JAG1 (AD)

Deep-set eyes, hypertelorism, upslanting palpebral fissures, posterior embryotoxon, anterior chamber anomalies, eccentric or ectopic pupils, chorioretinal atrophy, band keratopathy, cataracts, retinal pigment clumping, Axenfeld anomaly, microcornea, choroidal folds, strabismus, anomalous optic disc

Alport syndrome

COL4A5 (XLD); COL4A3 (AR/AD)

Anterior lenticonus, lens opacities, cataracts, pigmentary changes (“flecks”) in the perimacular region, corneal endothelial vesicles, corneal erosions

Angelman syndrome

UBE3A (IP); CH

Strabismus (most frequently exotropia), ocular hypopigmentation, refractive errors (astigmatism, hyperopia, myopia)

Bardet–Biedl syndrome

ARL6; BBS1; BBS2; BBS4; BBS5; BBS7; BBS9; BBS10; BBS12; CEP290; LZTFL1; MKKS; MKS1; SDCCAG8; TMEM67; TRIM32; TTC8; WDPCP (AR)

Rod-cone dystrophy onset by end of 2nd decade, retinitis pigmentosa, retinal degeneration, strabismus, cataracts

Beals syndrome

FBN2 (AD)

Ectopia lentis

Beaulieu–Boycott–Innes syndrome

THOC6 (AR)

Deep-set eyes, short palpebral fissures, upslanting palpebral fissures

Bohring–Opitz syndrome

ASXL1 (AD)

Prominent eyes, hypoplastic orbital ridges, hypertelorism, upslanting palpebral fissures, strabismus, retinal abnormalities, optic nerve abnormalities

Bone fragility and contractures; arterial rupture and deafness

PLOD3 (AR)

Shallow orbits, cataracts

Branchiooculofacial syndrome

TFAP2A (AD)

Lacrimal sac fistula, orbital dermoid cyst, iris pigment epithelial cyst, combined hamartoma of the retina and retinal pigment epithelium, upslanting palpebral fissures, telecanthus, hypertelorism, ptosis, lacrimal duct obstruction, iris coloboma, retinal coloboma, microphthalmia, anophthalmia, cataract, strabismus

Cardiofaciocutaneous syndrome

MAP2K2 (AD)

Ptosis, nystagmus, strabismus, downslanting palpebral fissures, hypertelorism, exophthalmos, epicanthal folds, optic nerve dysplasia, oculomotor apraxia, loss of visual acuity, absence of eyebrows, absence of eyelashes

Cohen syndrome

VPS13B (AR)

Downslanting palpebral fissures, almond-shaped eyes, chorioretinal dystrophy, decreased visual acuity, optic atrophy

Cornelia de Lange syndrome

NIPBL (AD); HDAC8 (XLD)

Synophrys, long curly eyelashes, ptosis

Cowden syndrome

PTEN (AD)

Cataract, angioid streaks

Cranioectodermal dysplasia

IFT122 (AR)

Telecanthus, hypotelorism, epicanthal folds, myopia (1 patient), nystagmus (1 patient), retinal dystrophy (1 patient)

Cutis laxa

ATP6V0A2; ALDH18A1 (AR)

Downslanting palpebral fissures, strabismus

Danon disease

LAMP2 (XLD)

Moderate central loss of visual acuity in males, normal to near-normal visual acuity in carrier females, fine lamellar white opacities on slit lamp exam in carrier females, near complete loss of peripheral retinal pigment in males, peppered pigmentary mottling of peripheral retinal pigment in carrier females, nonspecific changes on electroretinogram in carrier females

Deafness and myopia

SLITRK6 (AR)

High myopia

Desanto–Shinawi syndrome

WAC (AD)

Hypertelorism, downslanting palpebral issues, synophrys, deep-set eyes, astigmatism, strabismus

Desbuquois dysplasia

CANT1 (AR)

Prominent eyes, bulging eyes, congenital glaucoma

Donnai–Barrow syndrome

LRP2 (AR)

Hypertelorism, high myopia, loss of vision, iris coloboma, iris hypoplasia, cataract, enlarged globes, downslanting palpebral fissures, underorbital skin creases, retinal detachment, retinal dystrophy, prominent eyes

DOORS

TBC1D24 (AR)

Optic atrophy, blindness, high myopia, cataracts

Ehlers–Danlos syndrome

COL5A1 (AD); PLOD1 (AR); CHST14 (AR); ADAMTS2 (AR); B3GALT6 (AR); FKBP14 (AR)

Blue sclerae, ectopia lentis, epicanthal folds

Emanuel syndrome

CH

Hooded eyelids, deep-set eyes, upslanting palpebral fissures, strabismus

Fibrochondrogenesis

COL11A1 (AR)

Gyrate atrophy of choroid and retina with/without ornithinemia

OAT (AR)

Progressive chorioretinal degeneration, night blindness (onset in first decade, progressive loss of peripheral vision, blindness (onset in fourth or fifth decade), posterior subcapsular cataracts (onset in second or third decade)

Hamamy syndrome

IRX5 (AR)

Severe hypertelorism, laterally sparse eyebrows, myopia (progressive severe)

Homocystinuria

CBS (AR)

Ectopia lentis, glaucoma

Joint laxity; short stature; myopia

GZF1 (AR)

Exophthalmos, severe myopia, retinal detachment (some patients), iris coloboma (some patients), chorioretinal coloboma (some patients), glaucoma (1 patient)

Kaufman oculocerebrofacial syndrome

UBE3B (AR)

Blepharophimosis, ptosis, upward-slanting palpebral fissures, telecanthus, hypertelorism, astigmatism, strabismus, mild

Kenny–Caffey syndrome

FAM111A (AD)

Hyperopia (not myopia), microphthalmia, papilledema, corneal and retinal calcification, congenital cataracts (rare)

Kniest dysplasia

COL2A1 (AD)

Retinal detachment, cataracts, prominent eyes

Knobloch syndrome

COL18A1 (AR)

High myopia, vitreoretinal degeneration, retinal detachment (childhood), congenital cataract, syneresis, vitreous attachment at the disc, persistent foetal hyaloid vasculature, peripapillary atrophy, phthisis bulbi, band keratopathy, macular hypoplasia, irregular white dots at the vitreoretinal interface, visual loss, nystagmus

Lamb–Shaffer syndrome

SOX5 (AD)

Downslanting palpebral fissures, epicanthal folds, strabismus

Lethal congenital contracture syndrome

ERBB3 (AR)

High myopia, degenerative vitreoretinopathy

Leukodystrophy

POLR1C; POLR3A; POLR3B; GJC2 (AR)

Linear skin defects with multiple congenital anomalies

NDUFB11; COX7B (XLD)

Lacrimal duct atresia, nystagmus, strabismus

Loeys–Dietz syndrome

TGFBR1; TGFBR2 (AD)

Hypertelorism, exotropia, blue sclerae, proptosis

Macrocephaly/megalencephaly syndrome

TBC1D7 (AR)

Astigmatism

Marfan syndrome

FBN1 (AD)

Enophthalmos, ectopia lentis increased axial globe length, corneal flatness, retinal detachment, iris hypoplasia, early glaucoma, early cataracts, downslanting palpebral fissures, trabeculodysgenesis, primary (some patients), strabismus (some patients), exotropia (some patients), esotropia (rare), hypertropia (rare)

Marshall syndrome

COL11A1 (AD)

congenital cataracts, esotropia, retinal detachment, glaucoma, lens dislocation, vitreoretinal degeneration, hypertelorism, epicanthal folds

Microcephaly with/without chorioretinopathy; lymphedema; and/or mental retardation

KIF11 (AD)

Upslanting palpebral fissures, downslanting palpebral fissures (some patients), epicanthal folds (some patients), nystagmus, reduced visual acuity, hypermetropia, myopic astigmatism, hypermetropic astigmatism, corneal opacity, microcornea, microphthalmia, cataract, retrolenticular fibrotic mass, chorioretinopathy, retinal folds, falciform retinal folds, retinal detachment, temporal dragging of optic disc, retinal pigment changes (some patients), optic atrophy (uncommon)

Mohr–Tranebjaerg syndrome

TIMM8A (XLR)

Photophobia, cortical blindness, decreased visual acuity, constricted visual fields, abnormal electroretinogram

Mucolipidosis

GNPTAG (AR)

Fine corneal opacities

Muscular dystrophy

TRAPPC11; POMT; POMT1; POMT2; POMGNT1; B3GALNT2; FKRP; DAG1; FKTN(AR)

Cataracts, strabismus, alacrima (some patients)

Nephrotic syndrome

LAMB2 (AR)

Nystagmus, strabismus, microcoria, aplasia/atrophy of the dilatator pupillae muscle, hypoplasia of the iris and ciliary body, lenticonus posterior, blindness, decreased or absent laminin beta-2 immunoreactivity in tissues of the anterior eye

Noonan syndrome

A2ML1; BRAF; CBL; HRAS; KRAS; MAP2K1; MAP2K2; NRAS; PTPN11; RAF1; RIT1; SOS1; SHOC2; SPRED1 (AD)

Ptosis, hypertelorism, downslanting palpebral fissures, epicanthal folds, blue-green irides

Oculocutaneous albinism

TYR (AR)

Absent pigment in iris and retina, translucent iris, pink irides (childhood), blue-gray irides (adult), choroidal vessels visible, foveal hypoplasia, decreased visual acuity, strabismus, nystagmus, photophobia, high refractive errors (hyperopia, myopia, with-the-rule astigmatism), albinotic optic disc, misrouting of the optic nerves at the chiasm, absent stereopsis due to anomalous decussation at the optic chiasm, positive angle kappa (appearance of exotropia but no shift on cover test), asymmetric visual evoked potentials

Oculodentodigital dysplasia

GJA1 (AR)

Hypoplastic eyebrows, sparse eyelashes, telecanthus, short palpebral fissures, downslanting palpebral fissures, microphthalmia, microcornea, cataract, persistent pupillary membrane

Pallister–Killian syndrome

CH

Sparse eyebrows, sparse eyelashes, upslanting palpebral fissures, hypertelorism, ptosis, strabismus, epicanthal folds, cataracts, exophthalmos

Papillorenal syndrome

PAX2 (AD)

Retinal coloboma, optic nerve anomalies (coloboma, gliosis, absent optic nerve head), optic disc anomalies (dysplasia, excavation, hyperplasia, morning glory optic disc, hypoplasia), orbital cysts, microphthalmia, abnormal retinal pigment epithelium, abnormal retinal vessels, chorioretinal degeneration, retinal detachment (rare). retinal staphyloma (rare), retinal edema (rare), macular degeneration (rare), papillomacular detachment (rare), hyperpigmentation of the macula (rare), cystic degeneration of the macula (rare), posterior lens luxation (rare), lens opacity (rare)

Peters-plus syndrome

B3GLCT (AR)

Hypertelorism, Peter’s anomaly, anterior chamber cleavage disorder, nystagmus, ptosis, glaucoma, upslanting palpebral fissures, cataract, iris coloboma, retinal coloboma

Pitt–Hopkins syndrome

TCF4 (AD)

Deep-set eyes, strabismus, astigmatism, upslanting palpebral fissures

Pontocerebellar hypoplasia

CHMP1A (AR)

Astigmatism, esotropia, strabismus, hyperopia, nystagmus (some patients), cortical visual impairment (some patients), poor visual tracking (some patients)

Poretti–Boltshauser syndrome

LAMA1 (AR)

Strabismus, amblyopia, oculomotor apraxia, nystagmus, retinal atrophy, retinal dystrophy, retinal dysfunction, macular heterotopia

Prader–Willi syndrome

NDN (PC); SNRPN (IP); CH

Almond-shaped eyes, strabismus, upslanting palpebral fissures, hyperopia

Pseudoxanthoma elasticum

ABCC6 (AR)

Peau d’orange retinal changes (yellow-mottled retinal hyperpigmentation), angioid streaks of the retina (85% of patients), macular degeneration, visual impairment (50–70% of patients), central vision loss, colloid bodies, retinal haemorrhage, choroidal neovascularization, optic head drusen (yellowish-white irregularities of optic disc), owl’s eyes (paired hyperpigmented spots)

Renal hypomagnesemia

CLDN16; CLDN19 (AR)

Strabismus, nystagmus, hyperopia, astigmatism

SADDAN

FGFR3 (AD)

High myopia, exotropia

Schaaf–Yang syndrome

MAGEL2 (AD)

Esotropia, strabismus, almond-shaped eyes, short palpebral fissures, bushy eyebrows

Schimke immunoosseous dysplasia

SMARCAL1 (AR)

Corneal opacities, astigmatism

Schuurs–Hoeijmakers syndrome

PACS1 (AD)

Full, arched eyebrows, long eyelashes, hypertelorism, downslanting palpebral fissures, ptosis, nystagmus, strabismus

Schwartz–Jampel syndrome

HSPG2 (AR)

Narrow palpebral fissures, blepharophimosis, cataract, microcornea, long eyelashes in irregular rows, ptosis

Sengers syndrome

AGK (AR)

Cataracts (infantile), strabismus, glaucoma

Short stature; hearing loss; retinitis pigmentosa and distinctive facies

EXOSC2 (AR)

Deep-set eyes, short palpebral fissures, upslanting palpebral fissures, retinitis pigmentosa (2 patients), corneal dystrophy (2 patients, young-adult onset), glaucoma (1 patient), nystagmus (1 patient), strabismus (1 patient)

Short stature; optic nerve atrophy; and Pelger–Huet anomaly

NBAS (AR)

Thick and bush eyebrows, small orbits, bilateral exophthalmos, epicanthus, bilateral optic nerve atrophy, non-progressive decreased visual acuity, (in)complete achromatopsia, strabismus (some patients), hypertelorism (some patients), hypermetropia (rare), pigmented nevus (rare)

SHORT syndrome

PIK3R1 (AD)

Deep-set eyes, Rieger anomaly, telecanthus, glaucoma, megalocornea, cataracts

Short-rib thoracic dysplasia with/without polydactyly

WDR19 (AR)

Cataracts, attenuated arteries, macular anomalies

Shprintzen–Goldberg syndrome

SKI (AD)

Telecanthus, hypertelorism, proptosis, strabismus, downslanting palpebral fissures, ptosis, shallow orbits

Singleton–Merten syndrome

IFIH1 (AD)

Glaucoma

Small vessel brain disease with/without ocular anomalies

COL4A1 (AD)

Retinal arteriolar tortuosity, hypopigmentation of the fundus, episodic scotomas, episodic blurred vision, amblyopia (1 family), strabismus (1 family), high intraocular pressure (1 family). Reported in some patients: astigmatism, hyperopia, congenital cataracts, prominent or irregular Schwalbe line, iridocorneal synechiae, Axenfeld–Rieger anomalies, corneal opacities, microphthalmia, microcornea, iris hypoplasia, corectopia. Rare: decreased visual acuity, glaucoma, corneal neovascularization, polycoria, iridogoniodysgenesis, macular haemorrhage and Fuchs spots, peripapillary atrophy, choroidal atrophy

Smith–Magenis syndrome

RAI1 (AD)

Spastic paraplegia and psychomotor retardation with or without seizures

HACE1 (AR)

Strabismus, retinal dystrophy (some patients)

Split hand/foot malformation

CH

Stickler syndrome

COL2A1 (AD); COL11A1 (AD); COL9A1 (AR); COL9A2 (AR)

Retinal detachment, blindness, occasional cataracts, glaucoma, membranous (type I) vitreous phenotype

Syndromic mental retardation

SETD5 (AD); MBD5 (AD); USP9X (XLD); NONO (XLR); RPL10 (XLR); SMS (XLR); ELOVL4 (AR); KDM5C (XLR)

Synophrys, eyebrow abnormalities, upslanting and short palpebral fissures, epicanthal folds, mild hypertelorism, strabismus, cataracts, hypermetropia, astigmatism, poor vision

Syndromic microphthalmia

OTX2; BMP4 (AD)

Uni- or bilateral microphthalmia, uni- or bilateral anophthalmia, coloboma, microcornea, cataract, retinal dystrophy, optic nerve hypoplasia or agenesis

Temtamy syndrome

C12orf57 (AR)

Hypertelorism. “key-hole” iris, retina and choroid coloboma, dislocated lens (upward), downslanting palpebral fissures, arched eyebrows

White–Sutton syndrome

POGZ (AD)

Visual abnormalities, strabismus, astigmatism, hyperopia, optic atrophy, rod-cone dystrophy, cortical blindness

Zimmermann–Laband syndrome

KCNH1 (AD)

Thick eyebrows, synophrys, cataracts

AD autosomal dominant, AR autosomal recessive, XLR X linked recessive, XLD X linked dominant, CH chromosomal, IP imprinting defect

Table 5.1A

Ocular conditions associated with myopia

Ocular condition

Gene and inheritance pattern

Achromatopsia

CNGB3 (AR)

Aland Island eye disease

GPR143 (XLR)

Anterior segment dysgenesis

PITX3 (AD)

Bietti crystalline corneoretinal dystrophy

CYP4V2 (AD)

Blue cone monochromacy

OPN1LW; OPN1MW (XLR)

Brittle cornea syndrome

ZNF469; PRDM5 (AR)

Cataract

BFSP2; CRYBA2; EPHA2 (AD)

Colobomatous macrophthalmia with microcornea

CH

Cone dystrophy

KCNV2 (AD)

Cone rod dystrophy

C8orf37 (AR); RAB28 (AR); RPGR (XLR); CACNA1F (XLR)

Congenital microcoria

CH

Congenital stationary night blindness

NYX (XLR); CACNA1F (XLR); GRM6 (AR); SLC24A1 (AR); LRIT3 (AR); GNB3 (AR); GPR179 (AR)

Ectopia lentis et pupillae

ADAMTSL4 (AR)

High myopia with cataract and vitreoretinal degeneration

P3H2 (AR)

Keratoconus

VSX1 (AD)

Leber congenital amaurosis

TULP1 (AR)

Microcornea, myopic chorioretinal atrophy, and telecanthus

ADAMTS18 (AR)

Microspherophakia and/or megalocornea, with ectopia lentis and/or secondary glaucoma

LTBP2 (AR)

Ocular albinism

OCA2 (AR)

Primary open angle glaucoma

MYOC; OPTN (AD)

Retinal cone dystrophy

KCNV2 (AR)

Retinal dystrophy

C21orf2 (AR); TUB (AR)

Retinitis pigmentosa

RP1 (AD); RP2 (XLR); RPGR (XLR); TTC8 (AR)

Sveinsson chorioretinal atrophy

TEAD1 (AD)

Vitreoretinopathy

ZNF408 (AD)

Wagner vitreoretinopathy

VCAN (AD)

Weill–Marchesani syndrome

ADAMTS10 (AR); FBN1(AD); LTBP2 (AR); ADAMTS17 (AR)

AD autosomal dominant, AR autosomal recessive, XLR X linked recessive, CH chromosomal

Interestingly, several syndromic myopia genes were found in association to other ocular traits, such as CCT (ADAMTS2, COL4A3, COL5A1, FBN1) [14], and Fuchs’s dystrophy (TCF4) [15]. However, the majority of the genes causing syndromic myopia have not been linked to common forms of myopia, except for COL2A1 [16, 17] and FBN1 [18, 19]. Nevertheless, a recent study found an overrepresentation for syndromic myopia genes in GWAS studies on refractive error and myopia [20], implying their important role in myopia development.

5.4 Linkage Studies

Linkage studies have been successfully applied for many Mendelian disorders, although the success has been much more limited in complex traits. The linkage approach searches for cosegregation of genetic markers with the trait of interest in pedigrees [21]. Families with genetic variants which show an autosomal dominant inheritance pattern were also most successful for myopia linkage studies. Up to now, 20 MYP loci [22, 23, 24, 25] and several other loci [26, 27, 28, 29, 30, 31] are identified for (high) myopia. Fine mapping led to candidate genes, such as the IGF1 gene located in the MYP3 locus [32]. Linkage using a complex inheritance design found five additional loci [33, 34, 35, 36, 37].

Validation of candidate genes often resulted in no association, but other variants appeared associated with the non-Mendelian, common form of myopia. This hints towards a genetic overlap between Mendelian and common myopia [38]. As the GWAS era progressed, linkage studies fell by the wayside. Nevertheless, segregation analyses combined with linkage and next generation sequencing (i.e. whole exome sequencing) of regions in pedigrees with high myopia are, in theory, expected to facilitate the discovery of rare variants with large effects; an aspect which cannot be distilled from GWAS.

5.5 Candidate Gene Studies

In candidate gene studies the focus is on a gene with suspected biological, physiological or functional relevance to myopia, in particular high myopia. Although sometimes effective, candidate gene studies are limited by their reliance on this existing knowledge. Table 5.2 summarizes candidate gene studies on (high) myopia. Particularly notable are genes encoding extracellular matrix-related proteins (COL1A1, COL2A1 [16, 17] and MMP1, MMP2, MMP3, MMP9, MMP10 [59, 60]). For candidates such as PAX6 and TGFB1, the results were replicated in multiple independent extreme/high myopia studies and validated in a large GWAS meta-analysis in 2018, respectively [18, 76]. However in most other cases, the results were not independently validated: LUM and IGF1 failed to confirm an association [77, 78]. Interestingly, in a few cases the candidates were subsequently implicated in GWAS of other ocular traits: TGFβ2 and LUM for central corneal thickness (CCT), a glaucoma and keratoconus endophenotype [14], PAX6 with optic disc area [79] and HGF [80].
Table 5.2

Summary of candidate gene studies reporting positive association results with myopia

Gene symbol

Gene name

Hypothesized gene function

Associated phenotype

Ethnicity

Confirmation type (PMID)

Study (PMID)

Year

APLP2

Amyloid beta precursor like protein 2

Amacrine cell function modulation

Refractive error

Caucasian

n/a

Tkatchenko et al. [39] (26313004)

2015

BMP2K

Bone morphogenic protein-2-inducible protein kinase

Ocular development (embryogenesis) and retinal tissue remodelling

High myopia

Chinese

n/a

Liu et al. [40](19927351)

2009

CHRM1

Cholinergic receptor muscarinic 1

Target of atropine

High myopia (−6.5 dpt)

Han Chinese

Expression study found no association with CHRM1 (19262686) and finding has been debated (20414262)

Lin et al. [41, 42] (19753311)

2010

CHRM1

Cholinergic receptor muscarinic 1

Target of atropine

High myopia (−6.5 dpt)

Han Chinese

Expression study found no association with CHRM1 (19262686) and finding has been debated (20414262)

Lin et al. [43, 44] (19753311)

2009

cMET (alias HGFR)

Tyrosine-protein kinase met

Hepatocyte growth factor and its receptor

Paediatric myopia (<−0.5 dpt)

Chinese

Replication independent high myopia cohort (24766640)

Khor et al. [45] (19500853)

2009

COL1A1

Collagen type I alpha 1 chain

Extracellular matrix

High myopia (<−9.25 dpt)

Japanese

Multiple systemic meta-analyses with contradicting results (27162737; 26131177; 27588274)

Inamori et al. [46] (17557158)

2007

COL2A1

Collagen type II alpha 1 chain

Extracellular matrix

High myopia (−5 dpt)

Caucasian

No replication independent high myopia cohort (21993774)

Metlapally et al. [47] (19387081)

2009

COL2A1

Collagen type II alpha 1 chain

Extracellular matrix

Paediatric myopia (<−0.75 dpt)

Caucasian

No replication independent high myopia cohort (21993774)

Mutti et al. [48] (17653045)

2007

CRYBA4

Crystallin beta A4

Retinal and scleral remodelling

High myopia (<−8 dpt)

Chinese

No replication independent high myopia cohort (29263643)

Ho et al. [49] (22792142)

2012

HGF

Hepatocyte growth factor

Hepatocyte growth factor and its receptor

High myopia

Han Chinese

No replication independent high myopia cohort (19060265)

Han et al. [50] (16723436)

2006

HGF

Hepatocyte growth factor

Hepatocyte growth factor and its receptor

Refractive error

Caucasian

No replication independent high myopia cohort (19060265)

Veerappan et al. [51] (20005573)

2010

HGF

Hepatocyte growth factor

Hepatocyte growth factor and its receptor

High Myopia (−5 dpt)

Caucasian

No replication independent high myopia cohort (19060265)

Yanovitch et al. [52] (19471602)

2009

IGF1

Insulin-like growth factor 1

Hepatocyte growth factor and its receptor

High myopia (−5 dpt)

Caucasian

Systematic review and meta-analysis of studies in high myopics resulted in no association (28135889)

Metlapally et al. [53] (20435602)

2010

LAMA1

Laminin subunit alpha 1

Extracellular matrix

High myopia (<−6 dpt and axial length >26 mm)

Chinese

No replication independent high myopia cohort (29805427; 19668483)

Zhao et al. [54] (21541277)

2011

LUM

Lumican

Scleral and extracellular matrix remodelling

Extreme high myopia

Han Chinese

Meta-analysis of studies in high myopics resulted in no association (24927138)

Chen et al. [55] (19616852)

2009

LUM

Lumican

Scleral and extracellular matrix remodelling

High myopia

Han Chinese

Meta-analysis of studies in high myopics resulted in no association (24927138) and finding has been debated (20414262)

Lin et al. [41, 42] (19643966)

2010

LUM

Lumican

Scleral and extracellular matrix remodelling

High myopia (<−6.5 dpt)

Han Chinese

Meta-analysis of studies in high myopics resulted in no association (24927138)

Lin et al. [41, 42] (20010793)

2010

LUM

Lumican

Scleral and extracellular matrix remodelling

Extreme high myopia

Han Chinese

Meta-analysis of studies in high myopics resulted in no association (24927138)

Wang et al. [56] (16902402)

2006

MFN1

Mitofusin 1

Mitochondrial remodelling and apoptosis

Myopia

Caucasian

Expression study found association with myopia (27609161) and replication independent myopia cohort (26682159)

Andrew et al. [57] (18846214)

2008

MMP1

Matrix metallopeptidase 1

Extracellular matrix

Refractive error

Amish

No replication independent high myopia cohort (20435584; 23077567)

Wojciechowski et al. [58] (20484597)

2010

MMP1

Matrix metallopeptidase 1

Extracellular matrix

Refractive error

Caucasian

No replication independent high myopia cohort (20435584; 23077567)

Wojciechowski et al. [59] (23098370)

2013

MMP10

Matrix metallopeptidase 10

Extracellular matrix

Refractive error

Caucasian

No replication independent high myopia cohort (23077567)

Wojciechowski et al. [59] (23098370)

2013

MMP2

Matrix metallopeptidase 2

Extracellular matrix

Refractive error

Amish

Expression study found association with myopia (28402202; 29803830; 28900109; 24876280); no replication independent high myopia cohort (20435584; 23378725)

Wojciechowski et al. [58] (20484597)

2010

MMP2

Matrix metallopeptidase 2

Extracellular matrix

Refractive error

Caucasian

Expression study found association with myopia (28402202; 29803830; 28900109; 24876280); no replication independent high myopia cohort (20435584; 23378725)

Wojciechowski et al. [59] (23098370)

2013

MMP3

Matrix metallopeptidase 3

Extracellular matrix

Refractive error

Caucasian

Expression study found no association with myopia (24876280); No replication independent high myopia cohort (20435584; 23077567; 16935611)

Hall et al. [60] (19279308)

2009

MMP9

Matrix metallopeptidase 9

Extracellular matrix

Refractive error

Caucasian

No replication independent high myopia cohort (23077567)

Hall et al. [60] (19279308)

2009

MYOC

Myocilin

Cytoskeletal function

High myopia

Chinese

No replication independent high myopia cohort (22809227; 24766640)

Tang et al. [61] (17438518)

2007

MYOC

Myocilin

Cytoskeletal function

High myopia

Caucasian

No replication independent high myopia cohort (22809227; 24766640)

Vatavuk et al. [62] (19260140)

2009

MYOC

Myocilin

Cytoskeletal function

High myopia

Caucasian

No replication independent high myopia cohort (22809227; 24766640)

Zayats et al. [63] (19180258)

2009

PAX6

Paired box 6

Ocular development (embryogenesis)

High myopia

Han Chinese

Systemic review and meta-analysis of studies in high and extreme myopics resulted in replication (24637479)

Han et al. [64] (19124844)

2009

PAX6

Paired box 6

Ocular development (embryogenesis)

High myopia (<−9 dpt)

Japanese

Systemic review and meta-analysis of studies in high and extreme myopics resulted in replication (24637479)

Kanemaki et al. [65] (26604670)

2015

PAX6

Paired box 6

Ocular development (embryogenesis)

High myopia (axial length >26 mm)

Japanese

Systemic review and meta-analysis of studies in high and extreme myopics resulted in replication (24637479)

Miyake et al. [66] (23213273)

2012

PAX6

Paired box 6

Ocular development (embryogenesis)

High myopia (<−6 dpt and axial length >26 mm)

Han Chinese

Systemic review and meta-analysis of studies in high and extreme myopics resulted in replication (24637479)

Ng et al. [67] (19907666)

2009

PAX6

Paired box 6

Ocular development (embryogenesis)

Extreme high myopia

Chinese

Systemic review and meta-analysis of studies in high and extreme myopics resulted in replication (24637479)

Tsai et al. [68] (17948041)

2008

PSARL

Presenilins-associated rhomboid-like protein

Mitochondrial remodelling and apoptosis

Myopia

Caucasian

n/a

Andrew et al. [57] (18846214)

2008

SOX2OT

Sex-determining region Y-box 2 overlapping transcript

Neurogenesis and vertebrate development (embryogenesis)

Myopia

Caucasian

n/a

Andrew et al. [57] (18846214)

2008

TGFβ1

Transforming growth factor beta 1

Extracellular matrix remodelling

High myopia (<−8 dpt)

Chinese

Replication GWAS-meta-analysis on refractive error (29808027)

Khor et al. [69] (20697017)

2010

TGFβ1

Transforming growth factor beta 1

Extracellular matrix remodelling

High myopia

Chinese

Replication GWAS-meta-analysis on refractive error (29808027)

Lin et al. [70] (16807529)

2006

TGFβ1

Transforming growth factor beta 1

Extracellular matrix remodelling

High myopia

Indian

Replication GWAS-meta-analysis on refractive error (29808027)

Rasool et al. [71] (23325483)

2013

TGFβ1

Transforming growth factor beta 1

Extracellular matrix remodelling

High myopia (<−8 dpt)

Chinese

Replication GWAS-meta-analysis on refractive error (29808027)

Zha et al. [72] (19365037)

2009

TGFβ2

Transforming growth factor beta 2

Extracellular matrix remodelling

High myopia (<−6.5 dpt)

Han Chinese

Expression study found association with myopia (28900109; 29188062; 27214233; 24967344); expression study found no association with myopia (25112847)

Lin et al. [43, 44] (19710942)

2009

TGIF (alias TGIF1)

TGFB induced factor homeobox 1

Extracellular matrix remodelling

High myopia

Chinese

No replication independent high myopia cohort (19060265; 18172074; 17048038; 15223781)

Lam et al. [73] (12601022)

2003

TGIF1

TGFB induced factor homeobox 1

Extracellular matrix remodelling

High myopia

Indian

No replication independent high myopia cohort (19060265; 18172074; 17048038; 15223781)

Ahmed et al. [74] (24215395)

2014

UMODL1

Uromodulin like 1

Extracellular matrix

High myopia (<−9.25 dpt)

Japanese

No replication independent high myopia cohort (22857148)

Nishizaki et al. [75] (18535602)

2009

5.6 Genome-Wide Association Studies

Generally, linkage studies are limited to identification of genetic variants with a large effect on myopia [81]. Given the limited number of genes identified by linkage, it became apparent in the 2000s that identifying large numbers of additional myopia genes was more practical with genome-wide association studies (GWASes), since it has dramatically higher statistical power. GWASes have greatly enhanced our knowledge of the genetic architecture of (complex) diseases [82]. Most of the variants found via GWAS reside in non-exonic regions and their effect sizes are typically small [82, 83]. For GWAS, 200 k–500 k genetic markers are usually genotyped and a further >10 million “imputed”, taking advantage of the correlation structure of the genome. This approach is most effective for common variants (allele frequencies >0.01 in the population, although with larger reference panels, rarer alleles can also be detected).

Initially, GWASes for myopia were performed as a dichotomous outcome (i.e. case-control, Table 5.3). Since myopia constitutes a dichotomization of the quantitative trait spherical equivalent, considering the quantitative trait should be more informative for gene mapping. The first GWASes for spherical equivalent were conducted in 2010 [96, 97], with ~4000 individuals required to identify the first loci. The first loci to reach the genome-wide significance threshold (P < 5 × 10−8, the threshold reflecting the large number of statistical tests conducted genome-wide) were markers near the RASGFR1 gene on 15q25.1 (P = 2.70 × 10−9) and markers near GJD2 on 15q14 (P = 2.21 × 10−14). A subsequent analysis combining five cohorts (N = 7000) identified another locus at the RBFOX1 gene on chromosome 16 (P = 3.9 × 10−9) [98].
Table 5.3

Summary of case-control design GWASs and their highest associations with myopia

Authors (year)

Study description

Associations

Ethnicity

PMID

Nakanishi et al. (2009) [84]

Genome-wide association study (GWAS)

830 cases (pathologic myopia; AL >26 mm)

1911 controls

Strongest association with 11q24.1, 44kb upstream of the BLID gene and in the second intron of LOC399959

Japanese

19779542

Li et al. (2011) [85]

GWAS

287 cases (high myopia; SE ≤ −6D)

673 controls

Strongest suggestive association (P = 1.51 × 10−5) with 5p15.2 for an intronic SNP within the CTNND2 gene, but with replication in Japanese independent cohort (959 cases and 2128 controls; P = 0.035)

Chinese

Japanese

21095009

Lu et al. (2011) [86]

GWAS

1203 cases (high myopia; SE ≤ −6D)

955 controls (SE -0.50 D to +1.00 D)

Replication (P = 2.17 × 10−5) with a SNP in CTNND2 region

Chinese

21911587

Wang et al. [87] (2011)

SNP (n = 3) look-up in 11q24.1 and 21q22.3 regions

1255 cases (complex myopia; SE < −10.00 D <SE ≤−4.00 D)

563 cases (high myopia; SE ≤-6.00 D)

1052 controls (−0.50 D ≤ SE ≤ +2.00 D)

No statistically significant differences found for the genotype or allele frequencies of the three SNPs between the myopia cases and controls

Chinese

22194655

Yu et al. (2012) [88]

SNP (n = 27) look-up in 5p15 and 11q24 regions

321 cases (pathologic myopia; SE ≤ −6 D and AL > 26 mm)

310 control

Significantly associated SNPs in the CTNND2 gene and 11q24.1 region (P = 0.0126 and 0.0293, respectively) with pathological myopia, replicating previous findings for these loci

Chinese

22759899

Liu et al. (2014) [89]

Meta-analysis comprising the SNPs of all 5 previously published data on the CTNND2 gene and 11q24.1 region association with myopia

6954 cases

9346 controls

Significant association of 11q24.1 region with myopia (P = 0.013). No significant association with myopia for the CTNND2 gene (two SNPs tested: P = 0.725, P = 0.065)

Chinese

Japanese

24672220

Li et al. (2011) [85]

GWAS

102 cases (high myopia; SE ≤ −8 D with retinal degeneration)

335 controls

The strongest association (P = 7.70 × 10−13) was in a gene desert within the MYP11 region on 4q25

Chinese

21505071

Shi et al. (2011) [90]

GWAS

419 high myopia cases (≤−6D)

669 controls

The strongest association (P = 1.91 × 10−16) was in an intron within the MIPEP gene on 13q12

Han Chinese

21640322

Shi et al. (2013) [91]

GWAS

665 cases (high myopia; SE ≤ −6D)

960 controls

The strongest association (P = 8.95 × 10−14) was in the VIPR2 gene within the MYP4 locus, followed by three other variants in LD of the SNTB1 gene region (P = 1.13 × 10−8 to 2.13 × 10−11)

Han Chinese

23406873

Khor et al. (2013) [92]

GWAS meta-analysis of 4 Asian studies

1603 cases (“severe” myopia; SE ≤−6 D and AL ≥26 mm)

3427 controls

The SNTB1 gene was confirmed and a novel variant within the ZFHX1B gene (also known as ZEB2) reached genome-wide significance (P = 5.79 × 10−10)

East-Asian

23933737

Hosada et al. (2018) [93]

GWAS meta-analysis of 5 Asian studies

828 cases

3624 controls

Discovery (P = 1.46 × 10−10) and replication (P = 2.40 × 10−6) of the CCDC102B locus.

East-Asian

29725004

Meng et al. (2012) [94]

GWAS

192 cases (high myopia; SE ≤−6 D)

1064 controls

Confirmation of SNPs 3kb downstream of PPP1R3B in vicinity of MYP10 on 8p23 (P = 6.32 × 10−7) and MYP15 on 10q21.1 (P = 2.17 × 10−5)

European

23049088

Pickrell et al. (2016) [95]

GWAS

106,086 cases (Myopia “yes”; questionnaire)

85,757 controls (Myopia “no”; questionnaire)

More than 100 novel loci associated with myopia

European

27182965

These early efforts made it clear that individual groups would have difficulty in mapping many genes for spherical equivalent, motivating the formation of the Consortium for Refractive Error and Myopia (CREAM) in 2010, which included researchers and cohorts from the USA, Europe, Asia and Australia. They replicated SNPs in the 15q14 loci [99], which was further affirmed by other studies on both spherical equivalent and axial length alongside with the replication of the 15q25 locus [100, 101].

In 2013, two major GWAS meta-analyses on refractive error traits (spherical equivalent and age of spectacle wear) identified 37 novel loci (Table 5.4), with robust replication of GJD2, RFBOX1 and RASGFR1 in both meta-analyses. The first was the collaborative work of CREAM based on a GWAS meta-analysis on spherical equivalent, comprising 35 individual cohorts (NEuropean = 37,382; NSoutheastAsian = 12,332) [108]. 23andMe, a direct-to-consumer genetic testing company, performed the second major GWAS, replicating 8 of the novel loci found by CREAM and identifying another 11 novel loci based on a GWAS survival analysis of age of spectacle wear in 55,177 participants of European ancestry. To the surprise of some in the field, the effect sizes and direction of the effects of the loci found by these two groups were concordant despite the difference in phenotype definition and in scale: dioptres for CREAM and hazard ratios for 23andMe [109]. Subsequently, replication studies provided validation for the associated loci and highlighted two other suggestive associations. At this point, the implicated loci explained 3% of the phenotypic variance in refractive error [108, 110].
Table 5.4

Overview of the 37 novel loci found in 2013 by CREAM and 23andMe and subsequent replication

Locus #

Locus name

Discovery—P value HapMapII CREAM (2013)

Replication—P value HapMapII 23andMe (2013)

Replication—individual cohort (PMID)

Replication—P value 1000G CREAM&23 and Me (2018)

2

BICC1

2.06 × 10−13

n/a

Simpson et al. (2014) [102] (25233373), Yoshikawa et al. (2014) [103] (25335978)

1.07 × 10−18

3

LAMA2

1.79 × 10−12

6.80 × 10−53

Cheng et al. (2013) [104] (24144296), Simpson et al. (2014) [102] (25233373)

1.91 × 10−57

4

CD55

3.05 × 10−12

n/a

Cheng et al. (2013) [104] (24144296), Yoshikawa et al. (2014) [103] (25335978)

4.42 × 10−13

5

TOX/CA8

3.99 × 10−12

4.00 × 10−22

Simpson et al. (2014) [102] (25233373)

4.64 × 10−31

6

RDH5

4.44 × 10−12

1.30 × 10−23

 

4.06 × 10−43

7

CYP26A1

1.03 × 10−11

n/a

Yoshikawa et al. (2014) [103] (25335978)

7.49 × 10−10

8

RASGRF1

4.25 × 10−11

8.20 × 10−13

Oishi et al. (2013) [105] (24150758), Yoshikawa et al. (2014) [103] (25335978)

4.24 × 10−23

9

CHRNG

5.15 × 10−11

n/a

Tideman et al. (2016) [106] (27611182)

1.16 × 10−24

10

SHISA6

7.29 × 10−11

5.20 × 10−15

 

9.46 × 10−29

11

PRSS56

7.86 × 10−11

5.80 × 10−18

Simpson et al. (2014) [102] (25233373)

2.25 × 10−29

12

MYO1D

9.66 × 10−11

n/a

 

2.91 × 10−16

13

ZMAT4/SFRP1

3.69 × 10−10

1.80 × 10−18

Simpson et al. (2014) [102] (25233373), Yoshikawa et al. (2014) [103] (25335978)

1.02 × 10−27

14

A2BP/RBFOX1

5.64 × 10−10

4.10 × 10−26

Simpson et al. (2014) [102] (25233373), Tideman et al. (2016) [106] (27611182)

1.13 × 10−42

15

KCNQ5

4.18 × 10−9

2.70 × 10−25

Liao et al. (2017) [107] (28884119), Yoshikawa et al. (2014) [103] (25335978), Tideman et al. (2016) [106] (27611182)

5.43 × 10−48

16

PTPRR

5.47 × 10−9

n/a

 

1.81 × 10−13

17

GRIA4

5.92 × 10−9

n/a

Tideman et al. (2016) [106] (27611182), Yoshikawa et al. (2014) [103] (25335978)

8.84 × 10−12

18

TJP2

7.26 × 10−9

5.20 × 10−13

 

1.35 × 10−21

19

SIX6

1.00 × 10−8

n/a

 

2.12 × 10−8

20

LOC100506035

1.09 × 10−8

n/a

 

1.56 × 10−15

21

BMP2

1.57 × 10−8

n/a

Tideman et al. (2016) [106] (27611182), Yoshikawa et al. (2014) [103] (25335978)

3.11 × 10−9

22

CHD7

1.82 × 10−8

n/a

 

1.94 × 10−7

23

PCCA

2.11 × 10−8

n/a

 

1.68 × 10−7

24

CACNA1D

2.14 × 10−8

n/a

Tideman et al. (2016) [106] (27611182)

4.10 × 10−10

25

KCNJ2

2.79 × 10−8

n/a

 

5.53 × 10−13

26

RORB

4.15 × 10−8

n/a

 

1.07 × 10−11

27

LRRC4C

n/a

2.30 × 10−30

Tideman et al. (2016) [106] (27611182), Yoshikawa et al. (2014) [103] (25335978)

4.43 × 10−42

28

PABPCP2

n/a

1.50 × 10−14

 

1.05 × 10−17

29

BMP3

n/a

4.20 × 10−12

Simpson et al. (2014) [102] (25233373)

2.08 × 10−20

30

RGR

n/a

8.00 × 10−12

 

9.26 × 10−17

31

DLG2

n/a

1.70 × 10−11

 

8.85 × 10−15

32

ZBTB38

n/a

3.60 × 10−11

 

1.23 × 10−15

33

PDE11A

n/a

8.70 × 10−11

 

1.30 × 10−15

34

DLX1

n/a

1.40 × 10−10

 

2.77 × 10−16

35

KCNMA1

n/a

7.30 × 10−10

 

2.36 × 10−16

36

BMP4

n/a

1.10 × 10−9

Yoshikawa et al. (2014) [103] (25335978)

1.09 × 10−12

37

ZIC2

n/a

2.10 × 10−8

Oishi et al. (2013) [105] (24150758), Simpson et al. (2014) [102] (25233373), Tideman et al. (2016) [106] (27611182)

2.80 × 10−15

S-38*

B4GALNT2

n/a

8.30 × 10−7

Yoshikawa et al. (2014) [103] (25335978)

2.68 × 10−10

S-39*

EHBP1L1

n/a

2.10 × 10−7

Yoshikawa et al. (2014) [103] (25335978)

1.07 × 10−9

* These two loci were subthreshold (S) in the analysis in 2013, but exceeded genome-wide significance in 2018 using a larger sample size

The CREAM and 23andMe studies represented a large increase in sample size over the initial GWASs. Their meta-analysis approach was very effective in discovering new loci. This motivated joined efforts of CREAM and 23andMe, which resulted in a GWAS meta-analysis including 160,420 participants. Moreover, a denser imputation reference set was used (1000G phase 1 version 3), enabling better characterization of genetic variations. Although CREAM and 23andMe used different phenotypes (spherical equivalent and age at first spectacle wear, respectively) again the results were concordant and the new findings were replicated in an independent cohort with refractive error available (UK biobank, comprising 95,505 participants). Overall, this GWAS increased the number of risk loci to 161, explaining 7.8% of the phenotypic variance in refractive error. Very large sample sizes (millions) will be required to identify all of the loci contributing to myopia risk.

The genetic correlation was estimated to be 0.78 between European and Asian ancestry, suggesting that despite (1) large differences in the rate of myopia between these groups and (2) differences in the genetic ancestry of these groups, most of the genetic variation is in common. Figure 5.1 provides the chronological discovery of all associated loci and Fig. 5.2 shows the effect sizes of the established 161 loci.
Fig. 5.1

Historic overview of myopia gene finding. Overview of myopia gene finding in historic perspective. Genes identified using whole exome sequencing are marked as purple. Other loci (linkage studies, GWAS) are marked as red

Fig. 5.2

Effect sizes of common and rare variants for myopia and refractive error. Overview of SNPs and annotated genes found in the most recent GWAS meta-analysis [18]. X-axis displays the minor allele frequency of each SNP; y-axis displays the effect size of per individual SNP. The blue dots represent the novel loci discovered by Tedja et al. [18] and the pink dots represent the loci found by Verhoeven et al. [108], which now have been replicated

Several “endophenotypes” have been considered for myopia: spherical equivalent, axial length, corneal curvature and age of diagnosis of myopia. Axial length is a well-studied “endophenotype” which correlates strongly with refractive error. The first GWAS of axial length considered 4944 Asian ancestry individuals and identified a locus at 1q41. A subsequent meta-analysis combining data on 12,531 European and 8216 Asian ancestry individuals uncovered a further eight genome-wide significant loci at RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, ALPPL2, as well as confirming the 1q41 locus. Five of the axial length loci were also associated loci for refractive error. GWASs performed for corneal curvature [104, 111, 112, 113, 114] identified the loci FRAP1, CMPK1, RBP3 and PDGFRA; in the case of PDGFRA, associations have also been found with eye size. A study in 9804 Japanese individuals and replication in Chinese and European ancestry cohorts analysed three myopia-related traits (refractive error, axial length and corneal curvature). They replicated the association of GJD2 and refractive error as well as the association of SNPs in WNT7B for axial length and corneal curvature [114, 115]

5.7 Pathway Analysis Approaches

GWAS approaches improve our understanding of the molecular basis of traits by mapping individual loci. However, it is possible to place such loci into a broader context by applying pathway analysis approaches. In myopia, a retina-to-sclera signaling cascade has been postulated, but the specific molecular components were unclear. Recent GWASs have uncovered genes which lie along this pathway [108, 110, 116]—genetic changes at individual loci only make small changes to phenotype but collectively these perturbations are responsible for larger changes in the retina-to-sclera signaling cascade, ultimately explaining differences in refractive error from individual to individual.

Pathways inferred from the first large-scale CREAM GWAS [108, 110] included neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodelling (LAMA2, BMP2) and eye development (SIX6, PRSS56). The 23andMe GWAS identified an overlapping set of pathways: neuronal development (KCNMA1, RBFOX1, LRRC4C, NGL-1, DLG2, TJP2), extracellular matrix remodelling (ANTXR2, LAMA2), the visual cycle (RDH5, RGR, KCNQ5), eye and body growth (PRSS56, BMP4, ZBTB38, DLX1) and retinal ganglion cell (ZIC2, SFRP1) [117]. When considered in the context of known protein–protein interactions, many genes in these pathways are related to growth and cell cycle pathways, such as the TGF-beta/SMAD and MAPK pathways [118].

The most recent meta-analysis combining data from CREAM and 23andMe data taken together confirmed previous findings and offered additional insights [18]. In a gene-set analysis, several pathways were highlighted including “abnormal photoreceptor inner segment morphology” (Mammalian Phenotype Ontology (MP) 0003730); “thin retinal outer nuclear layer” (MP 0008515); “nonmotile primary cilium” (Gene Ontology (GO) 0031513); “abnormal anterior-eye-segment morphology” (MP 0005193) and “detection of light stimulus” (GO 0009583). The genes implicated in this large-scale GWAS were distributed across all cell types in the retina-to-sclera signaling cascade (neurosensory retina, RPE, vascular endothelium and extracellular matrix, Fig. 5.3). The larger GWAS also suggested novel mechanisms, including angiogenesis, rod-and-cone bipolar synaptic neurotransmission and anterior-segment morphology. Interestingly, a novel association was found at the DRD1 gene, supporting previous work linking the dopamine pathway to myopia.
Fig. 5.3

Schematic overview of known function in retinal cell types of refractive error and syndromic myopia genes according to literature. Bold: genes identified for both common refractive error and in syndromic myopia

5.8 Next Generation Sequencing

GWAS approaches have been highly effective in assessing the role of common variants in myopia but such methods cannot effectively characterize very rare genomic variants. Whole exome sequencing (WES) allows investigation of rare variants in exonic regions; due to cost, applications to date have primarily been in family studies or studies of early onset high myopia.

Studies employing WES to date have either focused on family designs (e.g. particular inheritance patterns such as X-linkage or conditions such as myopic anisometropia) or case-control studies of early onset high myopia [119, 120, 121, 122]. The WES-based approaches identified several novel mutations in known myopia genes (Table 5.5). For instance, Kloss et al. [131] performed WES on 14 families with high myopia, identifying 104 genetic variants in both known MYP loci (e.g. AGRN, EME1 and HOXA2) and in new loci (e.g. ATL3 and AKAP12) [131]. In the family studies, most variants displayed an autosomal dominant mode of inheritance [119, 123, 124, 130] although X-linked heterozygous mutations were found in ARR3 [126].
Table 5.5

Overview of genes and their mutations found by next generation sequencing

Gene

Pathway

Method

Inheritance Pattern

Mutation type

Mutation

Author (Year)

PMID

CCDC111

DNA transcription

Targeted sequencing and exome sequencing

Autosomal dominant

Missense

c.265T>G:p.Y89D in CCDC111

Zhao et al. (2013) [120]

23579484

NDUFAF7

Mitochondrial function

Genotyping and WES

Autosomal dominant

Missense

c.798C>G:p.D266E in NDUFAF7

Wang et al. (2017) [121]

28837730

P4HA2

Collagen synthesis

WES

Autosomal dominant

Missense

c.1147A>G:p.(K383E) in P4HA2

Napolitano et al. (2018) [119]

29364500

SCO2

Mitochondrial function

WES

Autosomal dominant

Missense

c.334C>T:p.R112W; c.358C>T:p.R120W in SCO2

Jiang et al. (2014) [123]

25525168

SCO2

Mitochondrial function

WES

Autosomal dominant

Nonsense

Missense

c.157C>T:p.Q53∗ in SCO2; c.341G>A:p.R114H; c.418G>A:p.E140K and c.776C>T:p.A259V) in SCO2

Tran-Viet et al. (2013) [124]

23643385

UNC5D

Cell signaling

WES

Autosomal dominant

Missense

c.1297C>T:p.R433C in UNC5D

Feng et al. (2017) [122]

28614238

BSG

Cell signaling

WES

Autosomal dominant

Missense

Splicing

Nonsense

c.889G>A:p.G297S; c.661C>T:p.P221S in BSG

c.205C>T:p.Q69X in BSG

c.415+1G>A in BSG

Jin et al. [125] (2017)

28373534

ARR3

Retina-specific signal transduction

WES

X-linked female-limited

Missense

c.893C>A:p.A298D; c.298C>T:p.R100∗ and c.239T>C:p.L80P in ARR3

Xiao et al. (2016) [126]

27829781

LOXL3

Transforming growth factor-beta pathway

WES

Autosomal recessive

Frameshift

c.39dup:p.L14Afs∗21; c.39dup:p.L14Afs∗21 and c.594delG:p.Q199Kfs∗35 in LOXL3

Li et al. [127] (2016)

26957899

SLC39A5

Transforming growth factor-beta pathway

WES

Autosome dominant

Autosome dominant

Nonsense

Missense

c.141C>G:p.Y47∗ in SLC39A5

c.911T>C:p.M304T in SLC39A5

Guo et al. [128] (2014)

24891338

SLC39A5

Transforming growth factor-beta pathway

WES

Autosome dominant

Missense

c.1238G>C:p.G413A in SLC39A5

Jiang et al. (2014) [123]

25525168

LRPAP1

Transforming growth factor-beta pathway

WES

Autosomal recessive

Frameshift, truncating

N202Tfs∗8 and I288Rfs∗118 in LRPAP1

Aldahmesh [129] et al. (2013)

23830514

LRPAP1

Transforming growth factor-beta pathway

WES

Autosomal recessive

Truncating

c.199delC:p.Q67Sfs∗8 in LRPAP1

Jiang et al. (2014) [123]

25525168

CTSH

Degradation of proteins in lysosomes

WES

Autosomal recessive

Frameshift, truncating

c.485_488del in CTSH

Aldahmesh [129] et al. (2013)

23830514

ZNF644

DNA transcription

WES

Autosomal dominant

Missense

I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A in ZNF644

Shi et al. [130] (2011)

21695231

ZNF644

DNA transcription

WES

Autosomal dominant

Missense

c.2014A>G:p.S672G; c.2048G>C:p.R683T and c.2551G>C:p.D851H

Jiang et al. (2014) [123]

25525168

104 novel genetic variants (73 rare)

WES in 14 families

Autosomal dominant

Non synonymous

Kloss et al. (2017) [131]

28384719

Both retinal dystrophies and ocular development disorders coincide with myopia. Sun et al. [132] investigated if there was a genetic link by evaluating a large number of retinal dystrophy genes in early onset high myopia. They examined 298 unrelated myopia probands and their families, identifying 29 potentially pathogenic mutations in COL2A1, COL11A1, PRPH2, FBN1, GNAT1, OPA1, PAX2, GUCY2D, TSPAN12, CACNA1F and RPGR with mainly an autosomal dominant pattern.

5.9 Environmental Influences Through Genetics

Although myopia is highly heritable within specific cohorts, dramatic changes in environment across many human populations have led to large changes in prevalence over time [133, 134, 135, 136]. The role of changes in socioeconomic status, time spent outdoors, education and near-work are now well established as risk factors for myopia, based on observational studies [137, 138, 139]. Education has proven the most influential and consistent factor, with a doubling in myopia prevalence when attending higher education compared to finishing only primary education [140, 141, 142]. There are two main areas where genetic studies can inform our understanding of the role of environment. Firstly, gene–environment studies can highlight where interactions exist. Secondly, observational studies only establish association and not causation—in some circumstances genetic data can be used to strengthen the case for an environmental risk factor causally (or not) influencing myopia risk (Mendelian randomization).

Gene–environment (GxE) interaction analyses examine whether genes operate differently across varying environments. GxE studies in myopia have focused primarily on education. An early study in North American samples examined GxE for myopia and the matrix metalloproteinases genes (MMP1-MMP10): a subset of SNPs were only associated with refraction in the lower education level [58, 59]. A subsequent study in five Singapore cohorts found variants in DNAH9, GJD2 and ZMAT4, which had a larger effect on myopia in a high education subset [143]. Subsequent efforts to examine GxE considered the aggregate effects of many SNPs together. A study in Europeans found that a genetic risk score comprising 26 genetic variants was most strongly associated with myopia in individuals with a university level education [144]. A study examining GxE in children considered near work and time outdoors in association with 39 SNPs and found weak evidence for an interaction with near work [144, 145]. Finally, a CREAM study was able to identify additional myopia risk loci by allowing for a GxE approach [19].

Mendelian randomization (MR) infers whether a risk factor is causally associated with a disease. MR exploits the fact that germline genotypes are randomly assigned at meiosis, to enable a “natural” randomized controlled trial. Since the assigned genotypes are independent of non-genetic confounding and are unmodified by disease processes, MR offers a better assessment of causality than that available from observational studies [146, 147].

Two MR studies found a causal effect of education on the development of myopia. One of the MR studies tested for causality bi-directionally [148]. Both found a larger effect through MR than that estimated from observational studies suggesting that confounding in observational studies may have been obscuring the true relationship [149]. As expected, there was little evidence of myopia affecting education (−0.008 years/dioptre, P = 0.6). Another study focused on the causality of low vitamin D on myopia due to controversy in the literature [150]. The estimated effects of vitamin D on refractive error were so small (Caucasians: −0.02 [95% CI −0.09, 0.04] dioptres (D) per 10 nmol/l increase in vitamin D concentration; Asians: 0.01 [95% CI −0.17, 0.19] D per 10 nmol/l increase) that the authors concluded that the true contribution of vitamin D levels to degree of myopia is probably zero and that previous observational findings were likely confounded by the effects of time spent outdoors.

5.10 Epigenetics

Epigenetics in refractive error and myopia is postulated to be important due to the known effects of environmental factors on refractive error and myopia development. Nevertheless, this field is still developing and some characteristics of epigenetics render it a difficult issue to unravel. Epigenetic features can be influenced by environmental factors and are time dependent and tissue specific. This complicates the study of these effects, since myopia and refractive errors develop during childhood and young adolescence and obtaining eye tissue, preferably retinal and scleral would be unethical. Furthermore, although some epigenetic processes are conserved across species, this is not always the case: making animal studies not always translational to humans.

Non-Coding RNAs and Myopia

The latest GWAS meta-analysis found 31 of 161 loci residing in or near regions transcribing (small) noncoding RNAs, thus hinting towards the importance of epigenetics [18, 151]. MicroRNAs, or miRNAs, are the best-characterized family of small non-coding RNAs. They are approximately 19–24 nucleotides in length in their mature form. They are able to bind to 3′ UTR regions on RNA polymers by sequence-specific post-transcriptional gene silencing; one miRNA can regulate the translation of many genes. MiRNAs have been a hot topic in the last years due to their potential clinical application: the accessibility of the retina for miRNA-based therapeutic delivery has great potential for the prevention and treatment of retinal pathologies [152]. Up to now, there have only been a handful of studies on miRNA and its role in myopiagenesis in humans, these are summarized in Table 5.6.
Table 5.6

Overview of microRNAs associated with myopia

MiRNA

SNP

Study design

Outcome

Author

MiR-328 binding site in 3′UTR of PAX6 gene

rs662702

High myopia case-control study (Ncase = 1083, ≤−6 D; Ncontrol 1096 ≥−1.5 D)

Down regulation effect on PAX6 expression with C allele, relative to T allele. OR for CC genotype 2.1 (P = 0.007). This effect was significant for extreme myopia (<−10 D) and not for high myopia

Liang et al. (2011) [153]

MiR-184

n.a.

MiR-184 region sequenced in 780 unrelated keratoconus patients and 96 unrelated Han southern Chinese patients with axial myopia under the hypothesis that axial myopia is associated with keratoconus, possibly under regulation of MiR-184

No miR-184 mutations were detected in the axial myopia cohort

Lechner et al. (2013) [154]

MiR-29a

rs157907

High myopia case-control study (Ncases = 254, ≤−6 D; Ncontrols = 300, −0.5 to 0.5 D). COL1A1 is possibly targeted by MiR-29a

The G allele of the rs157907 locus was significantly associated with decreased risk of severe myopia (<10 D; P = 0.04), compared to the A allele. rs157907 A/G might regulate miR-29a expression levels, but no functional studies have been conducted to confirm this hypothesis

Xie et al. (2016) [155]

Let-7i

rs10877885

High myopia case-control study (Ncases = 254, ≤−6 D; Ncontrols = 300, −0.5 to 0.5 D). COL1A1 is possibly targeted by Let-7i

No significant association with rs10877885 (C/T) was found with myopia risk

Xie et al. (2016) [155]

5.11 Implications for Clinical Management

Due to the high polygenicity of myopia and low explained phenotypic variance by genetic factors (7.8%), clinical applications derived from genetic analyses of myopia are currently limited. Risk predictions for myopia in children are based on family history, education level of the parents, the amount of outdoor exposure and the easily measurable refractive error and axial length.

Currently, we are able to make a distinction between high myopes and high hyperopes based on the polygenic risk scores derived from CREAM studies: persons in the highest decile for the polygenic risk score had a 40-fold-greater risk of myopia relative to those in the lowest decile.

A prediction model including age, sex and polygenic risk score achieved an AUC of 0.77 (95% CI = 0.75–0.79) for myopia versus hyperopia in adults (Rotterdam Study I–III) [18]. This AUC is similar to that achieved by modelling environmental factors only; the AUC for myopia incidence in a European child cohort was 0.78 considering parental myopia, 1 or more books read per week, time spent reading, no participation in sports, non-European ethnicity, less time spent outdoors and baseline AL-to-CR ratio [156]. To date, one study has assessed both environmental and genetic factors together and showed that modelling both genes and environment improved prediction accuracy [157]. Although these efforts to improve prediction are promising, a prediction-based approach will only be beneficial if randomized controlled trials of atropine therapy show that children with persistent myopic progression benefit from an earlier and higher dose of atropine administration. The additional costs of genetic testing and potentially invasive regime (collecting blood from children) also need to be taken into account.

5.12 Concluding Remarks

The scientific community has discovered more than 200 loci associated with myopia and its endophenotypes with a variety of approaches (linkage, candidate gene, GWAS, post-GWAS gene-based associations, next generation sequencing approaches, gene environment interactions and epigenetic approaches). With the rise of large biobanks, such as the UK Biobank [158], further GWAS meta-analyses between large consortia and companies will enable identification of many more genes. This will allow full elucidation of the molecular mechanism of myopiagenesis. Whole genome sequencing approaches will replace both GWAS and WES, and will elucidate the genetic structure which regulates the function of the myopia risk variants.

To fully understand the underlying mechanisms, the focus should lie on unraveling the genetic and epigenetic architecture of myopia by exploring interactions and effects of other “omics” in relevant tissue, i.e. multi-omics. This concept includes incorporation of methylomics, transcriptomics, proteomics and metabolomics. Future projects should focus on gathering more omics data on eye tissue. Next to the multi-omics approach, modelling gene–environment effects will tell us more about the genetic key players which are also susceptible to the environment. Furthermore, future functional studies interrogating the candidate genes and loci will point us to therapeutic solutions for myopia management.

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Authors and Affiliations

  1. 1.Department of OphthalmologyErasmus Medical CenterRotterdamThe Netherlands
  2. 2.Department of EpidemiologyErasmus Medical CenterRotterdamThe Netherlands
  3. 3.Department of Clinical GeneticsErasmus Medical CenterRotterdamThe Netherlands
  4. 4.Department of OphthalmologyRadboud University Medical CenterNijmegenThe Netherlands
  5. 5.Statistical GeneticsQIMR Berghofer Medical Research InstituteBrisbaneAustralia

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