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Panel-based targeted exome sequencing reveals novel candidate susceptibility loci for age-related cataracts in Chinese Cohort.

ABSTRACT: BACKGROUND:Age-related cataracts (ARC) is the most common blinding eye disease worldwide, and its incidence tend to become younger. However, the relationship between genetic factors and mechanisms is not fully understood. The aim of the study was to further clarify the relationship between ARC and genetic mechanisms in East Asian populations and to elucidate the pathogenesis. METHODS:The study collected 191 sporadic cataracts and 208 healthy people from the eastern provinces of China, with an average age of about 60 years. All participants were subjected to a comprehensive ophthalmic clinical examination and peripheral blood samples were collected and their genomic DNA was extracted. Mutations were screened among 792 candidate genes to enhance understanding of the disease through targeted capture and high-throughput sequencing. RESULTS:We identified novel candidate susceptibility gene, which may serve as a potential susceptibility factor leading to an increase in the incidence of age-related cataracts. Three novel loci are associated with age-related cataracts significant significance: rs129882 in DBH (p = 5.27E-07, odds ratio = 3.9), rs1800280 in DMD (p = 2.85E-06, odds ratio = 1.4) and rs2871776 in ATP13A2 (p = 4.18E-05, odds ratio = 0.04). Gene-gene interaction analysis revealed that the most significant interactions between genes include the interaction between DBH and TUB (rs17847537 in TUB, rs129882 in DBH, p-value = 2.12E-14), and the interaction between DBH and DMD (rs1800280 in DMD, rs129882 in DBH, p-value = 2.12E-14). Pathway analysis shows that the most significant processes are concentrated in response to light stimulation (adjusted p-Value = 5.56E-03), response to radiation (adjusted P-Value = 5.56E-03), abiotic stimulus (adjusted p-Value = 5.56E-03). eQTL analysis shows that DBH rs129882 could regulate the expression of DBH mRNA in various tissues including retina. CONCLUSION:Our study indicates rs129882 and rs1800280 loci are associated with age-related cataracts, which enlarge the gene map of age-related cataracts.

SUBMITTER: Li JK

PROVIDER: S-EPMC7336732 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Panel-based targeted exome sequencing reveals novel candidate susceptibility loci for age-related cataracts in Chinese Cohort.

Li Jian-Kang JK Li Li-Li LL Li Wei W Wang Zi-Wei ZW Gao Feng-Juan FJ Hu Fang-Yuan FY Zhang Sheng-Hai SH Qu Shou-Fang SF Huang Jie J Wang Lu-Sheng LS Wu Ji-Hong JH Chen Fang F

Molecular genetics & genomic medicine 20200426 7

<h4>Background</h4>Age-related cataracts (ARC) is the most common blinding eye disease worldwide, and its incidence tend to become younger. However, the relationship between genetic factors and mechanisms is not fully understood. The aim of the study was to further clarify the relationship between ARC and genetic mechanisms in East Asian populations and to elucidate the pathogenesis.<h4>Methods</h4>The study collected 191 sporadic cataracts and 208 healthy people from the eastern provinces of Ch ...[more]

PMID: 32337810

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Project description:BackgroundPanel-based targeted exome sequencing was used to analyze the genetic and clinical findings of targeted genes in a cohort of northeast Chinese with retinitis pigmentosa.MethodsA total of 87 subjects, comprising 23 probands and their family members (total patients: 32) with confirmed retinitis pigmentosa were recruited in the study. Panel-based targeted exome sequencing was used to sequence the patients and family members, all subjects with retinitis pigmentosa underwent a complete ophthalmologic examination.ResultsOf the 23 probands, the clinical manifestations include night blindness, narrowing of vision, secondary cataracts, choroidal atrophy, color blindness, and high myopia, the average age of onset of night blindness is 12.9 ± 14 (range, 0-65; median, 8). Posterior subcapsular opacities is the most common forms of secondary cataracts (nine cases, 39.1%), and peripheral choroidal atrophy is the most common form of secondary choroidal atrophy (12 cases, 52.2%). Of these probands with complication peripheral choroidal atrophy, there were eight probands (66.7%, 8/12) caused by the pathogenic variation in USH2A gene. A total of 17 genes and 45 variants were detected in 23 probands. Among these genes, the commonest genes were USH2A (40%; 18/45), RP1 (15.6%; 7/45), and EYS (8.9%; 4/45), and the top three genes account for 56.5% (13/23) of diagnostic probands. Among these variants, comprising 22 (48.9%) pathogenic variants, 14 (31%) likely pathogenic variants, and nine (20%) uncertain clinical significance variants, and 22 variants was discovered first time. Most of the mutations associated with RP were missense (53.3%, 24/45), and the remaining mutation types include frameshift (35.6%, 16/45), nonsense (6.7%, 3/45), and spliceSite (4.4%, 2/45). Among the probands with mutations detected, compound heterozygous forms was detected in 13 (56.5%, 13/23) probands, and digenic inheritance (DI) forms was detected in five (21.7%, 5/23) probands.ConclusionPanel-based targeted exome sequencing revealed 23 novel mutations, recognized different combinations forms of variants, and extended the mutational spectrum of retinitis pigmentosa and depicted common variants in northeast China.

Dataset Information

Panel-based targeted exome sequencing reveals novel candidate susceptibility loci for age-related cataracts in Chinese Cohort.

Publications

Panel-based targeted exome sequencing reveals novel candidate susceptibility loci for age-related cataracts in Chinese Cohort.

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