Analysis of genetically determined gene expression suggests role of inflammatory processes in exfoliation syndrome

BMC Genomics

Research Article

Ran Tao¹  Milam A. Brantley²  Daniel Berner³  Ursula Schlötzer-Schrehardt³  Peter S. Straub⁴  Max A. Breyer⁴  Anuar I. Konkashbaev⁴  Patrick Evans⁴  Julia Sealock⁴  Nancy J. Cox⁵  Jibril B. Hirbo⁵  Eric R. Gamazon⁶  Chiea C. Khor⁷  Francesca Pasutto⁸  André Reis⁸  Karen M. Joos⁹  Priyanka Pawar⁹ 

[1] Biostatistics, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA;Clare Hall and MRC Epidemiology Unit, University of Cambridge, CB2 0SL, Cambridge, UK;Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany;Genetic Medicine, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA;Genetic Medicine, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA;Vanderbilt Genetics Institute, 37232, Nashville, TN, USA;Genetic Medicine, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA;Vanderbilt Genetics Institute, 37232, Nashville, TN, USA;Clare Hall and MRC Epidemiology Unit, University of Cambridge, CB2 0SL, Cambridge, UK;Genome Institute of Singapore, 60 Biopolis St, 138672, Singapore, Singapore;Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, 91054, Erlangen, Germany;Vanderbilt Eye Institute, Vanderbilt University Medical Center, 37232, Nashville, TN, USA;

关键词: Exfoliation syndrome;    GWAS;    TWAS;    transcriptomics;    GTEx;    predicted expressions;   

DOI  :  10.1186/s12864-023-09179-7

 received in 2022-06-20, accepted in 2023-02-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundExfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. The largest global meta-analysis of XFS in 123,457 multi-ethnic individuals from 24 countries identified seven loci with the strongest association signal in chr15q22–25 region near LOXL1. Expression analysis have so far correlated coding and a few non-coding variants in the region with LOXL1 expression levels, but functional effects of these variants is unclear. We hypothesize that analysis of the contribution of the genetically determined component of gene expression to XFS risk can provide a powerful method to elucidate potential roles of additional genes and clarify biology that underlie XFS.ResultsTranscriptomic Wide Association Studies (TWAS) using PrediXcan models trained in 48 GTEx tissues leveraging on results from the multi-ethnic and European ancestry GWAS were performed. To eliminate the possibility of false-positive results due to Linkage Disequilibrium (LD) contamination, we i) performed PrediXcan analysis in reduced models removing variants in LD with LOXL1 missense variants associated with XFS, and variants in LOXL1 models in both multiethnic and European ancestry individuals, ii) conducted conditional analysis of the significant signals in European ancestry individuals, and iii) filtered signals based on correlated gene expression, LD and shared eQTLs, iv) conducted expression validation analysis in human iris tissues. We observed twenty-eight genes in chr15q22–25 region that showed statistically significant associations, which were whittled down to ten genes after statistical validations. In experimental analysis, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. TWAS genes for XFS were significantly enriched for genes associated with inflammatory conditions. We also observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases.ConclusionOur results implicate a role for connective tissues and inflammation pathways in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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Fig. 3