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A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.

ABSTRACT: Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measurements were included. We identify 47 genome-wide significant IOP-associated loci (P?

SUBMITTER: Choquet H

PROVIDER: S-EPMC5727399 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.

Choquet Hélène H Thai Khanh K KK Yin Jie J Hoffmann Thomas J TJ Kvale Mark N MN Banda Yambazi Y Schaefer Catherine C Risch Neil N Nair K Saidas KS Melles Ronald R Jorgenson Eric E

Nature communications 20171213 1

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measureme ...[more]

PMID: 29235454

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Project description:Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. It is associated with 23 multiple disease processes with primary open angle glaucoma (POAG) being the most prevalent. Due to its 24 complex, multifactorial nature, genetic predisposition is not completely understood thus, there is an urgent 25 need for additional investigations into the genetic regulation of IOP. Heterogenous stock (HS) outbred rats are 26 a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This 27 population is ideal for genome-wide association studies (GWAS) due to the accumulated recombinations 28 among well-defined haplotypes, the relatively high allele frequencies, access to a large collection of tissue 29 samples, and the large allelic effect size compared to human studies. The purpose of this study was to identify 30 genetic loci underlying elevated IOP using HS rats. Both male and female HS rats (N=1,812) were used in the 31 study. Genotyping-by-sequencing was used to obtain ~3.5M single nucleotide polymorphisms from each 32 individual. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to 33 determine a genome-wide significance threshold. We also estimated SNP heritabilities. Our GWAS results 34 identified three genome-wide significant loci for elevated IOP on chromosomes 1, 5, and 16. These loci 35 contained 7 genes in total including Tyr, Grm5, Ctsc, Rab38, MGC94199, Plekhf2, and Csmd1. We also 36 mapped expression quantitative trait loci (eQTLs) in HS rat eye tissue and discovered a cis-eQTL for Ctsc 37 among our significant loci. Tyr is the only gene that has been previously associated with human IOP. This 38 study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential 39 candidate genes for future functional testing. In summary, GWAS using HS rats is a powerful method for 40 identifying genome regions that harbor variants responsible for the variation in quantitative traits, such as IOP. 41 Additional studies are ongoing to further narrow the list of candidate genes in these intervals.

Dataset Information

A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.

Publications

A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.

Similar Datasets

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