A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14

Solouki, Abbas M; Verhoeven, Virginie J M; Duijn, Cornelia M. van; Verkerk, Annemieke J.M.H.; Ikram, M. Kamran; Hysi, Pirro G.; Despriet, Dominiek D. G.; Koolwijk, L. M. van; Ho, Lintje; Ramdas, Wishal D.; Czudowska, M. A.; Kuijpers, Robert W A M; Amin, Najaf; Struchalin, Maksim; Aulchenko, Yurii S.; Rij, Gabriël van; Riemslag, Frans C. C.; Young, Terri L.; Mackey, David A.; Spector, Timothy D.; Gorgels, Theo G. M. F.; Willemse-Assink, Jacqueline J. M.; Isaacs, Aaron; Kramer, R.; Swagemakers, Sigrid; Bergen, Arthur A. B.; Oosterhout, Andy A.L.J. van; Oostra, Ben A.; Rivadeneira, Fernando; Uitterlinden, André G.; Hofman, Albert; Jong, Paulus T. V. M. de; Hammond, Christopher J.; Vingerling, Johannes R.; Klaver, Caroline C.W.

doi:10.1038/ng.663

Cited by 179 publications

(171 citation statements)

References 37 publications

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“…Twin studies add further support, indicating heritability values between 0.5 and 0.90 (9)(10)(11). Genome-wide association studies have identified putative gene loci on chromosomes 13q (12) and 15q (13,14), as well as genetic variants in CTNND2, as being associated with myopia (15). Recently, a missense variant in LEPREL1 (encoding prolyl 3-hydroxylase 2 [P3H2]), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagen molecules, was associated with an autosomal-recessive form of high myopia and early-onset cataracts in an Israeli-Bedouin kindred (16).…”

Section: Introductionmentioning

confidence: 82%

SLITRK6 mutations cause myopia and deafness in humans and mice

Tekin¹,

Chioza²,

Matsumoto³

et al. 2013

J. Clin. Invest.

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Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome characterized by high myopia and sensorineural deafness. Our molecular investigation in 3 families led to the identification of 3 homozygous nonsense mutations (p.R181X, p.S297X, and p.Q414X) in SLIT and NTRK-like family, member 6 (SLITRK6), a leucine-rich repeat domain transmembrane protein. All 3 mutant SLITRK6 proteins displayed defective cell surface localization. High-resolution MRI of WT and Slitrk6-deficient mouse eyes revealed axial length increase in the mutant (the endophenotype of myopia). Additionally, mutant mice exhibited auditory function deficits that mirrored the human phenotype. Histological investigation of WT and Slitrk6-deficient mouse retinas in postnatal development indicated a delay in synaptogenesis in Slitrk6-deficient animals. Taken together, our results showed that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice and that its disruption leads to a syndrome characterized by severe myopia and deafness.

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Section: Introductionmentioning

confidence: 82%

SLITRK6 mutations cause myopia and deafness in humans and mice

Tekin¹,

Chioza²,

Matsumoto³

et al. 2013

J. Clin. Invest.

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“…Outlier MSE measurements were set as missing values. The average of the MSE in the right and left eyes was used in the analyses 43,44 , and likewise for AXL and RCC. The primary outcome measure was MSE at age 15.…”

Section: Discussionmentioning

confidence: 99%

Body Stature Growth Trajectories during Childhood and the Development of Myopia

et al. 2013

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Purpose-Stature at a particular age can be considered the cumulative result of growth during a number of preceding growth trajectory periods. We investigated whether height and weight growth trajectories from birth to age 10 years were related to refractive error at ages 11 and 15 years, and eye size at age 15 years. Design-Prospective analysis in a birth cohort.Participants-Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) United Kingdom birth cohort (minimum N=2,676).Methods-Growth trajectories between birth and 10 years were modeled from a series of height and weight measurements (N=6,815). Refractive error was assessed by non-cycloplegic autorefraction at ages 11 and 15 years (minimum N=4,737). Axial length and radius of corneal curvature were measured with an IOLmaster at age 15 years (minimum N=2,676). Growth trajectories, and an allelic score for 180 genetic variants associated with adult height, were tested for association with refractive error and eye size.Main outcome measures-Non-cycloplegic autorefraction at ages 11 and 15 years, and axial length and corneal curvature at age 15 years.Results-Height growth trajectory during the linear phase between 2.5-10 years was negatively associated with refractive error at 11 and 15 years (P<0.001), but explained <0.5% of inter-subject variation. Height and weight growth trajectories, especially shortly after birth, were positively associated with axial length and corneal curvature (P<0.001), predicting 1-5% of trait variation. Height growth after 2.5 years was not associated with corneal curvature, whilst the association with axial length continued up to 10 years. The height allelic score was associated with corneal curvature (P=0.03) but not with refractive error or axial length.Address for correspondence and requests for reprints: Dr Kate Northstone, Department of Social Medicine, Oakfield House, Oakfield Grove, Clifton, Bristol, BS8 1TQ, UK, Tel: +44 (0) Conclusions-Up to the age of 10 years, shared growth mechanisms contribute to scaling of eye and body size but minimally to the development of myopia.

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“…GJD2 is an established susceptibility gene for increased axial length and myopic refraction 11,23 . In the current study, these associations with GJD2 were replicated in our independent Japanese sample collections.…”

Section: Resultsmentioning

confidence: 99%

“…The associations with axial length and corneal curvature were successfully replicated in both Chinese and Caucasian cohorts. In addition, the WNT7B genotype strengthened the effects of GJD2, a widely replicated myopia susceptibility gene 11,23 . Furthermore, the WNT7B polymorphism rs10453441 was also significantly associated with extreme myopia.…”

Section: Discussionmentioning

confidence: 99%

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

et al. 2015

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Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, P meta ¼ 3.9 Â 10 À 13 ) and corneal curvature (P meta ¼ 2.9 Â 10 À 40 ) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR) meta ¼ 1.13, P meta ¼ 0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.

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A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14

Cited by 179 publications

References 37 publications

SLITRK6 mutations cause myopia and deafness in humans and mice

SLITRK6 mutations cause myopia and deafness in humans and mice

Body Stature Growth Trajectories during Childhood and the Development of Myopia

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

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