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Shivashankaran Chettiar, Swapan K. Nath, Murali R. Kuracha, Raminder Singh, Uppala Ratnamala, Uppala Radhakrishna; Genome-wide Linkage Study Of High-grade Myopia In Indian Families Reveal Polygenic Threshold Model Of Inheritance. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4442.
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Myopia (MYP), commonly referred to as nearsightedness, is one of the most common causes of visual disability throughout the world. Myopia may occur as an isolated genetic anomaly or it may be associated with other anomalies and/or syndromes. Among the elderly, the estimated worldwide prevalence of high-grade myopia is ~2.5 to 9.6%, but this prevalence varies with age, sex, occupation, ethnicity and other factors. Interestingly, the highest prevalence rates are amongst Asians, with 50-80% of their adult population being myopic. Although 17 susceptibility loci for either high or low grade myopia on various chromosomal regions have been mapped by linkage/association analysis, the pathophysiology of the mutation(s) causing gene(s) remains obscure.
We studied 27 multiplex autosomal dominant nonsyndromic Indian families each with over 12 affecteds and high-grade myopia with a refraction error in the either eye of ≤8D and a maximum age at onset of 12 years. We have recently confirmed the MYP1 locus (Invest Ophthalmol Vis Sci. 52:6814-9,2011) and documented three novel loci (Mol Vis. 17:2028-39,2011) using two large families with high-grade myopia. In a second stage, genome-wide linkage scan was performed using high-density Affymetrix Human SNP Array on two families (72 individuals) originating from Gujarat, India.
Linkage analysis identified three novel loci in family UR034 at 4p15.32-p14 ([NPL] 3.2; p = 0.008789), 11p11.2-q12.1 ([NPL] 3.5; p = 0.008789) and 13q14.11-q21.1 ([NPL] 3.2; p = 0.008789) between SNP markers rs1376184/rs1863325, rs950105/rs1376486 and rs347405/rs956122, respectively. Additionally, another novel locus was identified on 5q21 from family (UR035) with LOD score of 4.2.
The present study provides the first report of evidence of polygenic inheritance for high-grade myopia susceptibility loci in Indian families. Our results suggest that a high-density SNP-based procedure provides increased genomic coverage and better overall information content in contrast to microsatellite markers. Targeted sequence analyses of linked genomic regions and further study of polymorphic variants associated with MYP disorders are needed to understand role of polygenic inheritance in myopia and to determine how myopia can be prevented and/or treated.
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