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Baojian Fan, P Ferdina Marie Sharmila, N Soumittra, Sripriya Sarangapani, David S. Friedman, L Vijaya, Jonathan L Haines, Ronnie George, Janey L Wiggs; Whole Genome Sequencing of Large Consanguineous Pedigrees from South India Identifies New Candidate Genes for Lens Thickness. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1505.
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© ARVO (1962-2015); The Authors (2016-present)
Lens thickness is an important risk factor for cataract, myopia and glaucoma. Identifying genes contributing to this quantitative trait may effectively identify genetic risk factors predisposing to related complex diseases. Previously we performed genome-wide linkage analyses in 16 consanguineous pedigrees from South India and identified 3 novel genetic loci (3p22.3, 5q31.1 and 6q27) for lens thickness. The purpose of this study is to refine the candidate genes in these loci using whole genome sequencing.
279 individuals of 23 consanguineous pedigrees from South India were measured for lens thickness using Pentacam (Oculus, Inc., Lynnwood, WA). Whole genome sequencing was performed using the Standard Coverage PCR-Free WGS platform (read length: 2 x 150bp; coverage: 30x) at the Broad Institute. Homozygosity mapping was conducted using PLINK (v1.9) and detectRUNS (v0.9.6). Gene-based association test was performed for both rare and common variants using famSKAT-RC (v1.1.0). Age and sex were included as covariates. Multiple testings were corrected using the Bonferroni method.
Homozygosity mapping revealed 4, 22 and 3 candidate genes in the 3p22.3, 5q31.1 and 6q27 loci, respectively. Gene-based association test further refined the candidate genes to CLASP2 (P = 1.43×10-6) and FBXL2 (P = 1.41×10-6) in the 3p22.3 locus, CXXC5 (P = 1.04×10-8), CYSTM1 (P = 2.93×10-6), ECSCR (P = 7.76×10-8), MATR3 (P = 4.28×10-8), PAIP2 (P = 1.15×10-7), PSD2 (P = 1.69×10-8), SIL1 (P = 8.93×10-8) and UBE2D2 (P = 4.34×10-8) in the 5q31.1 locus, and PACRG (P = 1.07×10-6) in the 6q27 locus.
We identified 11 candidate genes for lens thickness. Among these genes, MATR3 and PAIP2 are highly expressed in the mouse lens. Mutations in SIL1 are known to cause Marinesco-Sjögren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. These findings provide new insights into the genetic etiologies of lens thickness and related diseases.
This is a 2021 ARVO Annual Meeting abstract.
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