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Ekaterina Hristova Yonova, Abhishek Nag, Pirro G Hysi, Katie M Williams, Cristina Venturini, Christopher J Hammond; Genome-wide association study of nuclear cataract finds suggestive association with a common variant in TRPM3. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5815.
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© ARVO (1962-2015); The Authors (2016-present)
The aim of this study was to identify common genetic variants and genes associated with nuclear cataract in a Caucasian population using genome-wide approaches. A recent genome wide association study (GWAS) meta-analysis identified two loci associated with age-related nuclear cataract in Asian populations. Further genetic loci remain to be found, given twin studies suggest a heritability of 48%.
Nuclear cataract was measured in 2265 twins (age ≥ 50) from the TwinsUK registry from Scheimpflug lens images, graded using an objective densitometry-based system. Genotypes were obtained using Illumina platforms (610K and 317K) and later imputed against the HapMapII panel. Next generation sequencing data was available for a subset of 940 individuals. Common genetic variants were analysed using a score-test-based analysis implemented in MERLIN, accounting for age, sex and family structure. All genes in close proximity to GWAS variants associated with nuclear cataract (n=63) were included for gene-centred association analysis using the sequencing data. In this case, the association between genes and nuclear cataract was tested using a rare variants burden test implemented in SKAT, adjusting for age and sex.
The most associated variant in our GWAS was rs9792446 (p=1.0e-7) in the second intron of the TRPM3 gene which encodes for a calcium channel. In mice, Trpm3 was found to be highly expressed in lens. A missense mutation in TRPM3 was recently reported to cause congenital cataract with high tension glaucoma. In addition, twelve other loci showed suggestive association with nuclear cataract (p<1.0e-5). We nominally replicated the association with CRYAA found previously in the Asian study (p=0.01 at rs870137). Analysis of rare variants using the burden test found 9 out of 63 genes to be associated with nuclear cataract (p<0.05). The most significantly associated gene was CALHM1 (p=0.001) which also encodes for a calcium channel.
Our results identify suggestive association between common TRPM3 variants as well as several other loci and nuclear cataract. We also found some evidence for an effect of rare variants in the CALHM1 gene on nuclear cataract. Ongoing replication studies will clarify the role of TRPM3 in age-related nuclear cataract, and larger samples will provide more power to discover further genetic associations.
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