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Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

ABSTRACT: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

SUBMITTER: Gharahkhani P

PROVIDER: S-EPMC7904932 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Gharahkhani Puya P Jorgenson Eric E Hysi Pirro P Khawaja Anthony P AP Pendergrass Sarah S Han Xikun X Ong Jue Sheng JS Hewitt Alex W AW Segrè Ayellet V AV Rouhana John M JM Hamel Andrew R AR Igo Robert P RP Choquet Helene H Qassim Ayub A Josyula Navya S NS Cooke Bailey Jessica N JN Bonnemaijer Pieter W M PWM Iglesias Adriana A Siggs Owen M OM Young Terri L TL Vitart Veronique V Thiadens Alberta A H J AAHJ Karjalainen Juha J Uebe Steffen S Melles Ronald B RB Nair K Saidas KS Luben Robert R Simcoe Mark M Amersinghe Nishani N Cree Angela J AJ Hohn Rene R Poplawski Alicia A Chen Li Jia LJ Rong Shi-Song SS Aung Tin T Vithana Eranga Nishanthie EN Tamiya Gen G Shiga Yukihiro Y Yamamoto Masayuki M Nakazawa Toru T Currant Hannah H Birney Ewan E Wang Xin X Auton Adam A Lupton Michelle K MK Martin Nicholas G NG Ashaye Adeyinka A Olawoye Olusola O Williams Susan E SE Akafo Stephen S Ramsay Michele M Hashimoto Kazuki K Kamatani Yoichiro Y Akiyama Masato M Momozawa Yukihide Y Foster Paul J PJ Khaw Peng T PT Morgan James E JE Strouthidis Nicholas G NG Kraft Peter P Kang Jae H JH Pang Chi Pui CP Pasutto Francesca F Mitchell Paul P Lotery Andrew J AJ Palotie Aarno A van Duijn Cornelia C Haines Jonathan L JL Hammond Chris C Pasquale Louis R LR Klaver Caroline C W CCW Hauser Michael M Khor Chiea Chuen CC Mackey David A DA Kubo Michiaki M Cheng Ching-Yu CY Craig Jamie E JE MacGregor Stuart S Wiggs Janey L JL

Nature communications 20210224 1

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants ...[more]

PMID: 33627673

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Project description:BackgroundRecent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP) or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG). The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients.MethodsThe study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG) patients with intra ocular pressure (IOP) > 21 mmHg and 199 non-HTG patients (presenting IOP < 20 mmHg), and 301 healthy controls from eastern India. Genotypes were determined by polymerase chain reaction and restriction digestion for three single nucleotide polymorphisms (SNPs): IL1A (-889C/T; rs1800587), IL1B (-511C/T; rs16944) and IL1B (3953C/T; rs1143634). Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method.ResultsNo significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T) where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025) for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T) was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039). On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003) while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022) compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015) and expected to confer protection.ConclusionThe study suggests that the genomic region containing the IL1 gene cluster influences the POAG pathogenesis mostly in non-HTG patients in eastern India. A similar study in additional and larger cohorts of patients in other population groups is necessary to further substantiate the observation.

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Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

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Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

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