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Author Spotlight: Unraveling the Pathogenesis of Age-Related Macular Degeneration and Discovering Potential Therapies
Published on: July 28, 2023
Integrative multiomic analysis unveils the molecular nexus of mitochondrial dysfunction in the pathogenesis of
Jianqi Chen1, Zhe Liu1, Yingting Zhu1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, Guangdong Province, China.
Abstract:
Mitochondrial dysfunction is linked to age-related macular degeneration (AMD), but its mechanisms and related molecular networks remain unclear. We explored the association between mitochondrial-related genes and AMD by integrating multiomic data. We acquired summary-level data on mitochondrial-related protein abundance, gene expression, and gene methylation from quantitative trait locus studies. Genetic associations with AMD were sourced from the International Age-related Macular Degeneration Genomics Consortium (discovery), FinnGen (replication), and UK Biobank (replication) studies. We used summary-data-based Mendelian randomization to assess the correlations between mitochondrial-related gene molecular characteristics and AMD. Furthermore, colocalization analysis was performed to ascertain if the detected signal pairings had a common causative genetic variation. Mitochondrial-related gene NFKB1 demonstrated a protective role in AMD (tier 1 evidence), whereas HSPA1A and HSPA1B genes were also associated with decreased AMD risk (tier 2 evidence). The methylation of cg09390974 and cg15409712 in NFKB1 was associated with increased NFKB1 expression, consistent with the protective effect on AMD risk, whereas inverse associations were observed between gene methylation and gene expression for HSPA1B (cg04835051 and cg16372051), supporting the risk roles of methylation in AMD. At circulating protein level, genetically predicted higher levels of HSPA1A (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.19-0.41, P < 0.001), HSPA1B (OR 0.13, 95% CI 0.06-0.27, P < 0.001), and NFKB1 (OR 0.43, 95% CI 0.27-0.68, P < 0.001) were inversely associated with AMD risk. These associations were corroborated in the colocalization analysis. We identified AMD-linked mitochondrial-related genes, potentially improving the understanding of its pathophysiological mechanisms and aiding the identification of novel pharmaceutical targets.
Insights
Mitochondrial dysfunction is linked to age-related macular degeneration (AMD). This study identified NFKB1, HSPA1A, and HSPA1B as mitochondrial-related genes associated with reduced AMD risk, offering potential therapeutic targets.
Area of Science:
- Genetics and Genomics
- Ophthalmology
- Molecular Biology
Background:
- Mitochondrial dysfunction is implicated in age-related macular degeneration (AMD) pathogenesis.
- The specific molecular mechanisms and gene networks underlying this association remain largely undefined.
- Understanding these links is crucial for developing effective AMD treatments.
Purpose of the Study:
- To investigate the association between mitochondrial-related genes and AMD.
- To explore the roles of gene expression, methylation, and protein levels in AMD risk.
- To identify novel molecular targets for AMD therapy.
Main Methods:
- Integrated multiomic data including protein abundance, gene expression, and methylation.
- Employed summary-data-based Mendelian randomization to assess genetic correlations.
- Utilized colocalization analysis to confirm shared genetic causality.
Main Results:
- NFKB1 showed a protective role in AMD (Tier 1 evidence).
- HSPA1A and HSPA1B genes were associated with decreased AMD risk (Tier 2 evidence).
- Specific methylation patterns in NFKB1 and HSPA1B correlated with gene expression and AMD risk.
- Genetically predicted higher protein levels of HSPA1A, HSPA1B, and NFKB1 were inversely associated with AMD risk.
Conclusions:
- Identified key mitochondrial-related genes (NFKB1, HSPA1A, HSPA1B) linked to AMD risk.
- Elucidated potential roles of gene expression, methylation, and protein levels in AMD.
- These findings enhance understanding of AMD pathophysiology and suggest novel therapeutic targets.
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