June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Whole Genome Sequencing of Large Consanguineous Pedigrees from South India Identifies New Candidate Genes for Lens Thickness
Author Affiliations & Notes
  • Baojian Fan
    Massachusetts Eye and Ear Infirmary Department of Ophthalmology, Boston, Massachusetts, United States
  • P Ferdina Marie Sharmila
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • N Soumittra
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • Sripriya Sarangapani
    SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai, India
  • David S. Friedman
    Massachusetts Eye and Ear Infirmary Department of Ophthalmology, Boston, Massachusetts, United States
  • L Vijaya
    Medical Research Foundation, Sankara Nethralaya, Chennai, India
  • Jonathan L Haines
    Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
  • Ronnie George
    Medical Research Foundation, Sankara Nethralaya, Chennai, India
  • Janey L Wiggs
    Massachusetts Eye and Ear Infirmary Department of Ophthalmology, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Baojian Fan, None; P Ferdina Marie Sharmila, None; N Soumittra, None; Sripriya Sarangapani, None; David Friedman, None; L Vijaya, None; Jonathan Haines, None; Ronnie George, None; Janey Wiggs, Aerpio (F), Allergan (C), Editas (C), Maze (C), Regenxbio (C)
  • Footnotes
    Support  NEI Grants R01EY027129; R21EY018149; P30EY014104; Research to Prevent Blindness; Massachusetts Lions Eye Research Fund; No.BT/PR10288/Med/12/381/2007, Department of Biotechnology, Government of India.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1505. doi:
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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)

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Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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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