Stephanie J Loomis1, Alison P Klein1,2,3, Kristine E Lee4, Fei Chen1, Samantha Bomotti1, Barbara Truitt5, Sudha K Iyengar5, Ronald Klein4, Barbara E K Klein4, Priya Duggal1. 1. a Department of Epidemiology , Johns Hopkins Bloomberg School of Public Health , Baltimore , MD , USA. 2. b Department of Oncology , Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins , Baltimore , MD , USA. 3. c Department of Pathology , Johns Hopkins School of Medicine , Baltimore , MD , USA. 4. d Department of Ophthalmology and Visual Sciences , University of Wisconsin School of Medicine and Public Health , Madison , WN , USA. 5. e Department of Epidemiology and Biostatistics , Case Western Reserve University , Cleveland , OH , USA.
Abstract
PURPOSE: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. METHODS: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. RESULTS: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10-6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10-5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10-6) and among never smokers (N = 790, p = 2.67 × 10-6). CONCLUSIONS: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
PURPOSE: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. METHODS: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. RESULTS: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10-6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10-5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10-6) and among never smokers (N = 790, p = 2.67 × 10-6). CONCLUSIONS: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Nathan Congdon; Karl W Broman; Hong Lai; Beatriz Munoz; Heidi Bowie; Donna Gilber; Robert Wojciechowski; Christine Alston; Sheila K West Journal: Invest Ophthalmol Vis Sci Date: 2004-07 Impact factor: 4.799
Authors: Ekaterina Yonova-Doing; Wanting Zhao; Robert P Igo; Chaolong Wang; Periasamy Sundaresan; Kristine E Lee; Gyungah R Jun; Alexessander Couto Alves; Xiaoran Chai; Anita S Y Chan; Mei Chin Lee; Allan Fong; Ava G Tan; Chiea Chuen Khor; Emily Y Chew; Pirro G Hysi; Qiao Fan; Jacqueline Chua; Jaeyoon Chung; Jiemin Liao; Johanna M Colijn; Kathryn P Burdon; Lars G Fritsche; Maria K Swift; Maryam H Hilmy; Miao Ling Chee; Milly Tedja; Pieter W M Bonnemaijer; Preeti Gupta; Queenie S Tan; Zheng Li; Eranga N Vithana; Ravilla D Ravindran; Soon-Phaik Chee; Yuan Shi; Wenting Liu; Xinyi Su; Xueling Sim; Yang Shen; Ya Xing Wang; Hengtong Li; Yih-Chung Tham; Yik Ying Teo; Tin Aung; Kerrin S Small; Paul Mitchell; Jost B Jonas; Tien Yin Wong; Astrid E Fletcher; Caroline C W Klaver; Barbara E K Klein; Jie Jin Wang; Sudha K Iyengar; Christopher J Hammond; Ching-Yu Cheng Journal: Commun Biol Date: 2020-12-11