Update on the Epidemiology and Genetics of Myopic Refractive Error

Justin C Sherwin; David A Mackey

Expert Rev Ophthalmol. 2013;8(1):63-87.

Abstract and Introduction

Abstract

While myopia is an increasingly common refractive error worldwide, its prevalence is greatest in urbanized regions in east Asia. Myopia is a complex multifactorial ocular disorder governed by both genetic and environmental factors and possibly their interplay. Evidence for a genetic role in myopia has been derived from studies of syndromal myopia, familial correlation studies and linkage analyses. More recently, candidate gene and genome-wide association studies have been utilized. However, a high proportion of the heritability of myopia remains unexplained. Most genetic discoveries have been for high myopia, with the search for genes underpinning myopia of lesser severity yielding fewer positive associations. This may soon change with the use of next-generation sequencing, as well as the use of epigenetics and proteomic approaches.

1 2 3 4 5 6 7

Next Section

Table 1. Prevalence of myopia in selected population-based studies.
Study (year), location	Age (years)	Analyzed (n)	Eligible (%)	Myopia (D) (SE)	Prevalence, % (95% CI)	Ref.
Andhra Pradesh Study (2009), South India	≥40	2522	85.4	≤-0.5	34.6 (33.1–36.1)^†	[36]
Baltimore Eye Study (1997), USA	50–80+	5028	79.2	≤-0.5	28.0 (white), 27.6 (black)^†	[217]
Barbados Eye Study (1999)	40–84	4036	84	≤-0.5	21.9 (20.6–23.2)	[38]
Beaver Dam Eye Study (1994), USA	43–86	4533	83.2	≤-0.5	26.2^‡	[218]
Beijing Eye Study (2005), China	≥40	4319	83.4	≤-0.5	22.9 (21.7–24.2)	[45]
Blue Mountains Eye Study (1999), Australia	49–97	3650	82.4	≤-0.5	14.0	[40]
Botucatu Eye Study (2009), Brazil	1–92	2454	81.8	≤-0.5	29.7 (24.9–35.0 [30–39 years]), 21 (15.8–27.3 [70+ years])	[219]
Central Australian Ocular Health (2010), Australia	30+	1653	67 [40+]	≤-0.5	11.1, 10.1 [40+]	[220]
Handan Eye Study (2009), China (north)	≥30	6491	85.9	≤-0.5	26.7 (25.6–27.8)	[46]
Hyderabad (1999), India	All ages	2321	92.0	≤-0.5	4.44 (2.14–6.75 [≤15 years]^†), 19.39 (16.54–22.24 [>15 years]^†)	[221]
Liwan Eye Study (2009), China (south)	≥50	1269	75.3	≤-0.5	32.3 (27.8–34.6)	[222]
Mashhad Eye Study (2011), Iran	All ages	2813	70.4	≤-0.5	3.64 (2.19–5.09 [≤15 years]), 22.36 (20.06–24.66 [>15 years])	[223]
Melbourne Visual Impairment Project (1999), Australia	40–80+	4506	83 (urban); 91 (rural)	≤-0.5	17.0 (15.8–18.0)	[63]
National Eye Survey (2004), Bangladesh	≥30	11,189	90.9	≤-0.5	23.8 (23.8, 23.8)^†	[224]
National Eye Survey (2011), Nigeria	≥40	13,599	89.9	≤-0.5	16.2 (15.2–17.1)	[44]
Nord-Trondelag (2002), Norway	20–25; 40–45	3137 (all)	NS	≤-0.5	35 (20–25); 33 (40–45)	[225]
Segovia Eye Study (2009), Spain	40–49	417	89	≤-0.5	25.4 (21.5–29.8)	[226]
Shihpai Eye Study (2003), Taiwan	≥65	1108	66.6	≤-0.5	19.4 (16.7–22.1)^†	[39]
Singapore Indian Eye Study (2011)	≥40	2805	75.6	≤-0.5	28.0 (25.8–30.2)^‡	[42]
Singapore Malay Eye Study (2008)	40–80	2974	78.7	≤-0.5	30.5 (30.2–30.7)^‡	[227]
Tajimi Study (2008), Japan	≥40	2829	78.1	≤0.5	41.5 (41.1–41.9)^†	[228]
Tanjong Pagar Study (2000), Singapore	≥40	1113	71.8	≤-0.5	38.7 (35.5–42.1)^‡	[47]

^†Age and gender-adjusted prevalence estimate.
^‡Age-adjusted prevalence estimate.
D: Diopter; NS: Not stated; SE: Spherical equivalent.

Table 2. Syndromes associated with high myopia.
Name	Frequency	Gene(s) involved	Mode of inheritance	MIM ID
Systemic syndrome
Alport syndrome	One in 50,000 newborns	COL4A3, COL4A4, COL4A5	80%: X-linked	Several
Cohen syndrome	Fewer than 1000 worldwide	COH1 (VPS13B)	Autosomal recessive	216550
Congenital spondoepiphyseal dysplasia	Rare: 175 cases reported in scientific literature	COL2A1	Autosomal dominant	183900
Cornelia De Lange syndrome	Possibly affects one in 10,000–30,000 newborns	NIPBL (50–60% of cases), DXS423E, CSPG6, RAD21	Most cases are sporadic	12247 (type 1); 300590 (type 2); 610759 (type 3); 614701(type 4)
Danon disease	Rare: exact prevalence unknown	LAMP2	X-linked dominant	300257
Ehlers Danlos syndrome	Combined (all types) one in 5000, with hypermobility and classic forms more common	There are more than ten types. Genes include: ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1 and COL5A2	Several different types	Several
Homocystinuria	Most common form affects at least one in 200,000–335,000 people worldwide, and more common in some countries (e.g., Qatar)	CBS, MTHFR, MTR, MTRR and MMADHC genes	Autosomal recessive inheritance	Several
Kniest syndrome	Rare: exact incidence is unknown	COL2A1	Autosomal dominant	156550
Knobloch syndrome	Rare	COL18A1 (type 1); ADAMS18 (type 2)	Autosomal recessive	267750 (type 1); 608454 (type 2)
Marfan syndrome	One in 5000	FBN1	Autosomal recessive has been confirmed in some instances. Approximately 25% arise from new mutations	154700
Marshall syndrome	Unknown	COL11A1	Autosomal dominant	154780
McCune–Albright syndrome	Between one in 100,000 and one in 1,000,000 worldwide	GNAS	Not inherited. Random mutation that occurs early in development (mosaicism)	174800
Noonan syndrome	One in 1000 to one in 2500 people	PTPN11, SOS1, KRAS, NRAS and BRAF genes	Autosomal dominant	Several types
Pitt–Hopkins syndrome	Rare: at least 50 people worldwide	TCF4	Autosomal dominant	610954
Potocki–Shaffer syndrome	Rare	ALX4	Proximal 11p deletion syndrome	601224
Rubinstein–Taybi syndrome	One in 100,000 to one in 125,000 newborns	When identified (half people no mutation) in CREBBP or EB300 or deletion on chromosome 16	Autosomal dominant pattern	180849 (type 1); 613684 (type 2)
Schwartz–Jampel syndrome (Type 2; also known as Stuve–Widemann syndrome MIM 151443)	Rare	SHSPG2 or LIFR	Either autosomal dominant or heterozygote manifestation	255800 (type 1); 601559 (type 2)
Shprintzen–Goldberg syndrome	Rare	FBN1	Unknown: familial inheritance is rare	182212
Smith–Magenis syndrome	At least one in 25,000 individuals	Deletion on chromosome 17 associated with RAI1 gene	Typically not inherited	182290
Stickler syndrome	One in 7500–9000 newborns	COL2A1, COL9A1, COL11A1 and COL11A2	Autosomal dominant inheritance	Several
Weill–Marchesani syndrome	Rare; estimated prevalence approximately one in 100,000	ADAMTS10 and FBN1	Autosomal dominant or autosomal recessive	277600 (type 1); 608328 (type 2)
Ocular syndrome
Achromatopsia 3	Rare	CNGB3	Autosomal recessive	262300
Brittle cornea syndrome	Unknown	Mutations in ZNF469 (type 1) or PRDM5 (type 2)	Autosomal recessive 614161 (type 21); 614170 (type 2)
Choroideremia	One in 50,000 to one in 100,000 people	CHM	X-linked recessive	303100
Coloboma	One in 10,000	PAX2, PAX6	Autosomal dominant and autosomal recessive both proposed	120200
Cone–rod dystrophy (retinitis pigmentosa)	One in 2500–7000	Several	Several types	Several types
Familial exudative vitreoretinopathy	Prevalence is unknown	FZD4, LRP5 and NDP genes	Autosomal dominant	133780
Myelinated nerve fibers	Unknown	None identified	Possibly autosomal dominant	159500
Wagner syndrome	Rare: approximately 50 families identified worldwide	VCAN	Autosomal dominant	143200
X-linked retinitis pigmentosa 2	Rare	RP2	X-linked	312600
X-linked Bornholm eye disease	Rare: higher in Danish ancestry	NA	X-linked	300843
X-linked congenital stationary night blindness	Unknown	NYX and CACNA1F	X-linked	31500

Data from OMIM³⁰¹ and the National Organization for Rare Disorders.³⁰²
MIM: Mendelian inheritance in man; NA: Not applicable.

Table 3. List of genetic loci for myopia/refractive error.
Study (year)	Locus	MIM ID	Location	Inheritance Pattern	Myopia severity	Age of onset	Ref.
Schwartz et al. (1990)	MYP1	310460	Xq28	X-linked recessive	High: -6.75 to -11.25 D	Early: 1.5–5 years	[229]
Young et al. (1998)	MYP2	160700	18p11.31	Autosomal dominant	High: -6 to -21 D	Early: 6.8 years (mean)	[230]
Young et al. (1998)	MYP3	603221	12q21-q23	Autosomal dominant	High: -6.25 to -15 D Average SE: -9.47 D	Early: 5.9 years (mean)	[230]
Paluru et al. (2003)	MYP5	608474	17q21-q22	Autosomal dominant	High: -5.5 to -50 D Average SE: -13.925 D	Early: 8.9 years (mean)	[231]
Stambolian et al. (2004)	MYP6	608908	22q12	NA	Mild-to-moderate: -1.00 D or lower	NA	[232]
Hammond et al. (2004)	MYP7	609256	11p13	NA	-12.12 to +7.25 D Mean SE: +0.39 D	NA	[233]
Hammond et al. (2004); Andrew et al. (2008)	MYP8	609257	3q26	NA	-12.12 to +7.25 D Mean SE: +0.39 D Range: -20 to +8.75 D	NA	[233,234]
Hammond et al. (2004)	MYP9	609258	4q12	NA	-12.12 to +7.25 D Mean SE: +0.39 D	NA	[233]
Hammond et al. (2004)	MYP10	609259	8p23	NA	-12.12 to +7.25 D Mean SE: +0.39 D	NA	[233]
Zhang et al. (2005)	MYP11	609994	4q22-q27	Autosomal dominant	High: -5 to -20 D	Early: before school age	[235]
Paluru et al. (2005)	MYP12	609995	2q37.1	Autosomal dominant	High: -7.25 to -27 D Mean SE: -14.46 D	Early: before 12 years of age	[236]
Zhang et al. (2006)	MYP13	300613	Xq23-q25	X-linked recessive	High: -6 to -20 D	Early: before school age	[237]
Wojciechowski et al. (2006)	MYP14	610320	1p36	NA	Moderate-to-high: -3.46 D (average)	NA	[238]
Nallasamy et al. (2007)	MYP15	612717	10q21.1	Autosomal dominant	High: -7.04 D (average)	Early: 6–16 years	[239]
Lam et al. (2008)	MYP16	612554	5p15.33-p15.2	Autosomal dominant	High: -7.13 to -16.86 D (range of averages)	NA	[240]
Naiglin et al. (2002), Paget et al. (2008)	MYP17, formerly MYP4	608367	7q15	Autosomal dominant	High: -13.05 D (average)	NA	[159,160]
Yang et al. (2009)	MYP18†	255500	14q22.1-q24.2	Autosomal recessive	High: -13.5 D (average right eye)	Early childhood	[241]
Ma et al. (2010)	MYP19^†	613969	5p13.3-p15.1	Autosomal dominant	High: -11.59 D (average)	Early: average age of myopia diagnosis 6.9 years (range: 4–11 years)	[242]
Shi et al. (2011)	MYP20^†	614166	13q12.12	Autosomal dominant	High: -10.64 D (average right eye)	NA	[243]
Shi et al. (2011)	MYP21^†	614167	1p22.2	Autosomal dominant caused by heterozygous mutation in the ZNF644 gene	High: -7.51 to -11.49 D (right eye)	Early: 3–4 years	[161]

^†Not yet formally recognized by HUGO Gene Nomenclature Committee.
MIM: Mendelian Inheritance in Man; NA: Not applicable.

Table 4. Selected candidate genes and their association with myopia in studies of humans.
Gene symbol	Gene name	Chromosomal location	MIM ID	Studies with a positive association	Studies with no association	Reason for being candidate
BDNF	Brain derived neurotrophic factor	11p14.1	113505		Mutti et al. (2007)¹⁵⁷	Associated with syndromic myopia
BMP2	Bone morphogenetic protein 2	20p12.3	112261	Liu et al. (2009)²⁴⁴		Function
CHRM1	Cholinergic receptor, muscarinic 1	11q12.3	118510	Lin et al. (2009)²⁴⁵		Function
COL1A1	Collaged type 1 α 1	17q21.31–q22	120150	Inamori et al. (2007)¹⁷¹	Liang et al. (2007)²⁴⁶	Function
COL2A1	Collagen type 2 α 1	12q13.11–q13.2	120140	Mutti et al. (2007)¹⁵⁷	Wang et al. (2012)¹⁸⁴	Associated with syndromic myopia
COL11A1	Collagen type 11 α 1	1p21.1	120280		Yip et al. (2011)²⁴⁷	Function
COL18A1	Collagen type 18 α 1	21q22.3	120328		Mutti et al. (2007)¹⁵⁷; Yip et al. (2011)²⁴⁷	Associated with syndromic myopia
CRYBA4	Crystallin β A4	22q11.2–q13.1	123631	Ho et al. (2012)²⁴⁸		Near MYP6 locus
DCN	Decorin	12q21.33	125255		Yip et al. (2011)²⁴⁹; Wang et al. (2006)¹⁸⁶	Proteoglycan gene
DSPG3/EPYC	Dermatan sulfate proteoglycan 3/epiphycan	12q21.33	601657		Chen et al. (2009)₁₇₂; Wang et al. (2006)¹⁸⁶; Wang et al. (2009)²⁵⁰; Yip et al. (2011)²⁴⁹	Function
EGR1	Early growth response 1	5q31.2	128990		Li et al. (2008)²⁵¹	Function
FBN1	Fibrillin 1	15q21.1	134797		Yip et al. (2011)²⁴⁷	Associated with syndromic myopia
FGF-2	FGF-2	4q27–q28	134920		Mutti et al. (2007)¹⁵⁷; Lin et al. (2009)²⁵²	Associated with syndromic myopia
FMOD	Fibromodulin	1q32.1	600245	Majava et al. (2007)¹⁷³	Paluru et al. (2004)²⁵³; Lin et al. (2009)²⁵²	Function
HGF	HGF	7q21.11	142409	Han et al. (2006)¹⁷⁸; Veerappan et al. (2010)¹⁷⁷; Yanovitch et al. (2009)¹⁷⁹	Wang et al. (2009)¹⁸⁷	Animal studies
IGF1	IGF-1	12q22–q24.1	147440	Mak et al. (2012)¹⁷⁶; Metlapally et al. (2010)¹⁸⁰	Rydzanicz et al. (2011)²⁵⁴	Function
IGFBP3	IGF-binding protein 3	7p12.3	146732		Mak et al. (2012)¹⁷⁶	Function
IGFBP4	IGF-binding protein 4	17q21.2	146733		Mak et al. (2012)¹⁷⁶	Function
LAMA1	Laminin α 1	18p11.31–p11.23	150430	Zhao et al. (2011)²⁵⁵	Sasaki et al. (2007)²⁵⁶	Function
LUM	Lumican	12q21.33	600616	Majava et al. (2007)¹⁷³; Chen et al. (2009)¹⁷²	Dai et al. (2012)²⁵⁷; Paluru et al. (2004)²⁵³; Wang et al. (2006)¹⁸⁶	Function
CMET	Met pro-oncogene (hepatocyte growth factor receptor)	7q31.2	164860	Yanovitch et al. 2009¹⁷⁹; Han et al. 2006¹⁷⁸	Schache et al. 2009²⁵⁸; Wang et al. 2009¹⁸⁷	Function
MMP1	Matrix metalloproteinase 1	11q22.2	120353	Wojciechowski et al. (2010)¹⁷⁴	Nakanishi et al. (2011)²⁵⁹	Function
MMP2	Matrix metalloproteinase 2	16q12.2	120360	Wojciechowski et al. (2010)¹⁷⁴	Nakanishi et al. (2011)²⁵⁹; Leung et al. (2011)²⁶⁰	Function
MMP3	Matrix metalloproteinase 3	11q22.2	185250	Hall et al. (2009)¹⁷⁵	Nakanishi et al. (2011)²⁵⁹; Liang et al. (2006)²⁶¹	Function
MMP9	Matrix metalloproteinase 9	20q13.12	120361	Hall et al. (2009)¹⁷⁵	Wojciechowski et al. (2010)¹⁷⁴	Function
MYOC	Myocilin	1q24.3	601652	Vatavuk et al. (2009)²⁶²	Dai et al. (2012)²⁵⁷; Zayats et al. (2009)²⁶³	Within MYOC locus
OPTC	Opticin	1q31-32	605127	Majava et al. (2007)¹⁷³; Wang et al. (2009)²⁵⁰		Function
PAX6	Paired box gene 6	11p13	607108	Hammond et al. (2006)²³³; Han et al. (2009)²⁶⁴; Hewitt et al. (2007)²⁶⁵; Liang et al. (2011)²⁶⁶; Tsai et al. (2008)²⁶⁷	Mutti et al. (2007)¹⁵⁷; Dai et al. (2012)²⁵⁷; Simpson et al. (2007)²⁶⁸	Associated with syndromic myopia within MYP7 locus
PLOD1	Procollagen–lysine, 2-oxoglutarate 5-dioygenase	1p36.22	153454		Yip et al. (2011)²⁴⁷	Associated with syndromic myopia
RARA	Retinoic acid receptor-α	17q21.2	180240		Veerappan et al. (2009)²⁶⁹	Function
SERPINI2	Serine protease inhibitor member 2	3p26.1	605587	Hysi et al. (2012)²⁷⁰		Identified through previous linkage
SOX2	Sry-Box 2	3q26.33	184429		Simpson et al. (2007)²⁶⁸	Function/identified through linkage
TGIF	TGF-β-induced factor	18p11.31	602630	Lam et al. (2003)¹⁸⁵	Hasumi et al. (2006)¹⁸⁹; Pertile et al. (2008)¹⁸⁸; Scavello et al. (2004)¹⁹²; Wang et al. (2009)¹⁸⁷	Within MYP2 locus
TGFB1	TGF-β1	19q13.2	190180		Hayashi et al. (2007)¹⁹⁰; Wang et al. (2009)¹⁸⁷	Function
TGFB2	TGF-β2	1q41	190220	Lam et al. (2003)¹⁸⁵; Lin et al. (2009)²⁵²		Function
TIMP1	Tissue inhibitor of metalloproteinase 1	Xp11.23	305370		Liang et al. (2006)²⁶¹; Wojciechowski et al. (2010)¹⁷⁴	Function
TIMP2	Tissue inhibitor of metalloproteinase 2	17q25	188825		Leung et al. (2011)²⁶⁰; Wojciechowski et al. (2010)¹⁷⁴	Function
TIMP3	Tissue inhibitor of metalloproteinase 3	22q12.1–q13.2	188826		Leung et al. (2011)²⁶⁰; Wojciechowski et al. (2010)¹⁷⁴	Function
TIMP4	Tissue inhibitor of metalloproteinase 4	3q25	601915		Wojciechowski et al. (2010)¹⁷⁴	Function
UMODL1	Uromodulin-like 1	21q22.3	613859		Zhu et al. (2012)²⁷¹	Previous linkage to loci
VDR	Vitamin D receptor	12q13.11	601769	Mutti et al. (2011)¹⁸²; Annamaneni et al. (2011)¹⁸³		Function

MIM: Mendelian Inheritance in Man.

Table 5. Genome-wide association studies and myopia/refractive error.
Study (year)	Primary group	Replication group	Ethnicity	Phenotype	Gene symbol	Location	Marker(s)	Ref.
Fan et al. (2012)	Singapore	NA	Chinese and Malay	High myopia and axial length	ZC3H11B	1q41	rs4373767	[79]
Hysi et al. (2010)	Netherlands	UK, Australia. Replicated in Japanese²⁷²	Caucasian	Ocular refraction	GJD2, ACTC1	15q14	rs634990	[194]
Li et al. (2011)	Singapore	Japanese other Chinese group²⁰⁰	Singaporean Chinese	High myopia	CTNND2	5p15	rs12716080; rs6885224	[199]
Li et al. (2011)	China	NA. This was replicated²⁷³	Han Chinese	High myopia	No known genes in region, but expressed sequence tags exist	4q25	rs10034228	[274]
Nakinishi et al. (2009)	Japan	NA	Japanese	High myopia	BLID LOC399959	11q24.1	rs577948	[210]
Shi et al. (2011)	China	NA	Han Chinese	High myopia	Locus contains three genes (MIPEP, C1QTNF9B-AS1 and C1QTNF9B)	13q12.12	rs9318086. Five other SNPs also significant	[243]
Solouki et al. (2010)	UK	Australia, The Netherlands. Replicated in Japanese²⁷²	Caucasian	Ocular refraction	RASGRF1	15q25.1	rs939658, rs8027411	[195]

An unpublished GWAS recently found 19 significant (p < 5 × 10⁻⁸) associations with myopia, 17 of which were novel.¹⁹⁷ Most of the associations (13; 68.4%) were located within or near genes known to be associated with eye development, neuronal development and signaling, the retinal visual cycle of the retina and general eye morphology: DLG2, KCNMA1, KCNQ5, LAMA2, LRRC4C, PRSS56, RBFOX1, RDH5, RGR, SFRP1, TJP2, ZBTB38 and ZIC2.
NA: Not applicable; SNP: Single-nucleotide polymorphism.