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Hasenin Al-khersan, Alan Kwong, Michael A Grassi; Mutations in MERTK are not associated with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1842.
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© ARVO (1962-2015); The Authors (2016-present)
While genome-wide association studies have begun to elucidate the genetic basis of age-related macular degeneration (AMD), full understanding of the pathology of AMD is complicated by the heterogeneous character of the disease. Thus, further identification of genetic associations in AMD will advance our understanding of disease pathology and therapeutic targets. Mutations in the MER Tyrosine Kinase (MERTK) gene cause an accumulation of debris in the subretinal space and have been implicated in autosomal recessive retinitis pigmentosa (RP). We identified an RP family with a novel nonsense MERTK mutation. Compound heterozygous members of this family with two pathogenic MERTK variants have RP. Interestingly, an obligate heterozygous carrier in this family with only the novel nonsense mutation had AMD. Hence, in this study we hypothesized that pathogenic heterozygous variations in MERTK may predispose to AMD.
Whole-genome sequence data from 4,869 age- and sex-matched case-control samples from the University of Michigan Kellogg Eye Center, the AREDS and AREDS2 studies from the National Eye Institute, the University of Pennsylvania, and the Michigan Biobank were queried for MERTK variants. After filtering for contamination, non-European ancestry, genotype mismatch, technical duplicates, and disease criteria, the final data set contained 4,787 samples: 2,394 Large Drusen, Geographic Atrophy (GA), Choroidal Neovascularization (CNV), and Mixed GA/CNV cases, and 2,393 controls. SNPs and indels were called with GotCloud and variants annotated using Variant Effect Predictor (VEP) build 84.
An average depth of 6x coverage was achieved in the whole-genome data set. In the sequenced data, 2,062 variants were annotated in MERTK: 2,014 non-coding, 14 synonymous, 33 missense, and 1 splice donor (rs371956016, c.2189+1G>T). No nonsense mutations were identified. Of the identified genetic variation in MERTK only the splice donor variant was predicted to be a ClinVar pathogenic variant. However, this variant was called only in one control and in none of the cases.
Though mutations in MERTK have been associated with RP, the present study suggests that mutations in MERTK do not cause AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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