Dataset Information

Exome Array Analysis of Nuclear Lens Opacity.

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.

SUBMITTER: Loomis SJ

PROVIDER: S-EPMC5851868 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Exome Array Analysis of Nuclear Lens Opacity.

Loomis Stephanie J SJ Klein Alison P AP Lee Kristine E KE Chen Fei F Bomotti Samantha S Truitt Barbara B Iyengar Sudha K SK Klein Ronald R Klein Barbara E K BEK Duggal Priya P

Ophthalmic epidemiology 20171128 3

<h4>Purpose</h4>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.<h4>Methods</h4>We analyzed Illumina ...[more]

PMID: 29182452

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Project description:PurposeCataract is the most prevalent cause of blindness in Nepal. Several epidemiologic studies have associated cataracts with use of biomass cookstoves. These studies, however, have had limitations, including potential control selection bias and limited adjustment for possible confounding. This study, in Pokhara City, in an area of Nepal where biomass cookstoves are widely used without direct venting of the smoke to the outdoors, focuses on preclinical measures of opacity while avoiding selection bias and taking into account comprehensive data on potential confounding factors.MethodsUsing a cross-sectional study design, severity of lenticular damage, judged on the LOCS (Lens Opacities Classification System) III scales, was investigated in women (n = 143), aged 20 to 65 years, without previously diagnosed cataract. Linear and logistic regression analyses were used to examine the relationships with stove type and length of use. Clinically significant cataract, used in the logistic regression models, was defined as a LOCS III score ≥2.ResultsUsing gas cookstoves as the reference group, logistic regression analysis for nuclear cataract showed evidence of relationships with stove type: for biomass stoves, the odds ratio was 2.58 (95% confidence interval, 1.22 to 5.46); and for kerosene stoves, the odds ratio was 5.18 (95% confidence interval, 0.88 to 30.38). Similar results were found for nuclear color (LOCS III score ≥2), but no association was found with cortical cataracts. Supporting a relationship between biomass stoves and nuclear cataract was a trend with years of exposure to biomass cookstoves (p = 0.01). Linear regression analyses did not show clear evidence of an association between lenticular damage and stove types. Biomass fuel used for heating was not associated with any form of opacity.ConclusionsThis study provides support for associations of biomass and kerosene cookstoves with nuclear opacity and change in nuclear color. The novel associations with kerosene cookstove use deserve further investigation.

Project description:Background and purposeThe genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.MethodsDiscovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.ResultsGene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6).ConclusionsExome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Dataset Information

Exome Array Analysis of Nuclear Lens Opacity.

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Exome Array Analysis of Nuclear Lens Opacity.

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