The macula, located near the retina's center in the human eye, is responsible for providing critical functions, such as central, sharp vision. In general, the macular thickness decreases with age, and structural changes in the macula are associated with many eye diseases, including age-related macular degeneration (AMD) and glaucoma. In most cases, reduced macular thickness is found in both AMD and glaucoma.
Epidemiological studies have identified many factors associated with macular thickness, including age, gender, body mass index, smoking, and myopia (near-sighted). Moreover, racial differences in macular thickness have been observed in several studies. Overall, white people tend to have the thickest macula, followed by individuals of Asian and African descent, respectively. It has also known that macular thickness is a highly heritable trait. Thus, identifying genetic factors that influence macular thickness aids in uncovering the biological mechanisms regulating this trait and may also help improve our understanding of related eye diseases.
Researchers performed the first genome-wide association study (GWAS) of macular thickness to achieve this goal. In total, 68,423 individuals (discovery phase n=59,814, replication phase n=8,609) from the UK Biobank cohort participated in this study. Macular thickness was measured as the average macular thickness within the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid outermost circle (diameter = 6 mm) for each eye. After removing outliers, the average macular thickness of both eyes was used for downstream analysis. If only the macular thickness of one eye was available, this measurement was used as a duplicate for the final value. Among the participants, the macular thickness values are normally distributed with an overall mean of 261.9 (SD=13.6) μm. The average macular thickness in the discovery and replication sets is 262.0 (SD=13.6) μm (range: 190.9–328.0) and 261.8 (SD=13.9) μm (range: 191.4–327.7), respectively. In the GWAS, 139 genetic loci associated with macular thickness were identified with at genome-wide significance, which included rs17421627 (LINC00461) , rs3138142 (RDH5), rs17279437( SLC6A20), rs11576909 (MGAT4EP - LOC148709), rs7033598 (MIR31HG,MTAP), rs5442 (GNB3), rs1947075 (ARHGAP22), rs17507554 (NEDD9, TMEM170B).
Of the ones identified, many help explain how AMD could develop. Rs3138142, resides in a region RDH5 and has previously been associated with AMD. RDH5 is a member of the retinol family, which is a group of enzymes that is involved in the visual cycle. RDH5 is also associated with myopia and refractive error. Rs17279437 is located in an exon of SLC6A20 and has previously been associated with urinary and blood metabolites. SLC6A20 has been associated with iminoglycinuria, a condition that affects the ability to reabsorb amino acids, such as proline, in the kidney and is highly expressed in the human eye. This is the first study that provides insights into the genetic architecture of macular thickness and may explain the beginnings of related eye diseases, such as AMD.
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