Genome-wide association studies: applications and insights gained in Ophthalmology

Abstract

Genome-wide association studies (GWAS) use high-throughput genotyping technologies to genotype thousands of single-nucleotide polymorphisms (SNPs) and relate them to the development of clinical and quantitative traits. Their use has been highly successful in the field of ophthalmology, and since the advent of GWAS in 2005, many genes not previously suspected of having a role in disease have been identified and the findings replicated. We conducted an extensive literature review and describe the concept, design, advantages, and limitations of GWAS and provide a detailed description of the applications and discoveries of GWAS in the field of eye disease to date. There have been many novel findings revealing previously unknown biological insights in a diverse range of common ocular conditions. GWAS have been a highly successful modality for investigating the pathogenesis of a wide variety of ophthalmic conditions. The insights gained into the pathogenesis of disease provide not only a better understanding of underlying disease mechanism but also offer a rationale for targeted treatment and preventative strategies. Expansive international collaboration and standardised phenotyping will permit the continued success of this investigative technique.

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“…Also, corneal transplantation as a procedure has a high usage of steroids to prevent graft rejection that can lead to secondary complications [ 11 ]. Genetic studies of corneal diseases have mostly been restricted to the identification of the typical gene mutation/s [ 12 ] with little advancement towards the understanding of the cellular mechanisms involved. Moreover, most of the insights into corneal disease pathology obtained thus far are from the investigations carried out using immortalized cell lines or engineered animal models [ 13 , 14 ], which are unable to fully capitulate the human conditions, thereby lacking disease relevant mechanistic insights.…”

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“…These provide an output of somewhere between 500,000 and 2,500,000 SNPs for that individual, but obviously do not include all the common genetic variants (given there are around 3 billion base pairs in the human genome). The missing data is therefore imputed using 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 GWAS have now been successfully performed on a range of ophthalmic diseases (21,22). The earliest and arguably the most 'successful' GWAS to date has been within the ophthalmic field; the discovery of the association of CFH with agerelated macular degeneration was reported in three independent cohorts in 2005 (23-25), one of which was a GWAS, and has since been replicated in dozens of studies across the world.…”

“…Significance thresholds are set at less than p ≤ 5 10 -8 to reduce the possibility of GWAS have now been successfully performed on a range of ophthalmic diseases (21,22). The earliest and arguably the most 'successful' GWAS to date has been within the ophthalmic field; the discovery of the association of CFH with agerelated macular degeneration was reported in three independent cohorts in 2005 (23-25), one of which was a GWAS, and has since been replicated in dozens of studies across the world.…”