Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes

It is difficult to get evidence from randomized trials of a causal relationship between steroid hormones produced by the adrenal gland and gonad and retinal neurodegenerative disorders (RND). In this study, genetic variations of aldosterone (Aldo), androstenedione (A4), progesterone (P4), hydroxyprogesterone (17-OHP), and testosterone/17β-estradiol (T/E2) were obtained from genome-wide association studies as instrumental variables. Mendelian randomization (MR) analysis was used to assess the impact on the risk of RND, including glaucoma (8,591 cases and 210,201 controls), diabetic retinopathy (DR, 14,584 cases and 202,082 controls) and age-related macular degeneration (AMD, 14,034 cases and 91,214 controls). As the main method, inverse variance weighted results suggest that the increased glaucoma risk was affected by T/E2 (OR = 1.11, 95% CI, 1.01–1.22, P = 0.03), which was further validated by other methods (PWM= 0.03, PMLE= 0.03, PMR-RAPS= 0.03). In the replicated stage, the causal relationship between T/E2 and glaucoma was verified based on the MRC-IEU consortium (P = 0.04). No impact of Aldo, A4, P4, 17-OHP, and T/E2 was observed for the risk of DR (P > 0.05) and AMD (P > 0.05). The heterogeneity test (P > 0.05) and pleiotropy test (P > 0.05) verified the robustness of the results. Our results suggest that T/E2 has a suggestive effect on the glaucoma risk. However, the genetic evidence based on a large sample does not support the effect of steroid hormones on DR and AMD risk. Further studies are vital to assess the possibility of steroid hormones as targets for prevention and treatment.

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“…Through pathway analysis, Youngblood et al. identified E2 as an upstream regulator of IOP-related genes such as TES ( 43 ). Jojua et al.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation reveals the influence of steroid hormones on the risk of retinal neurodegenerative diseases

Liu

Fan²,

Hu³

et al. 2023

Front. Endocrinol.

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“…Specifically, rs13399656 in SPTBN1 was the top finding in the sex-difference associations. This gene was previously recognized as a target for β-estradiol as the top upstream regulator [ 60 ]. Similarly, rs1808828 mapped to ABLIM3 and rs11738813 in ARHGEF28 were identified as intronic variants mapped in genes involved in estrogen signaling pathway [ 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the polygenic architecture of hearing problems in adults

et al. 2023

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Background Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies. Methods Leveraging the UK Biobank, the Nurses’ Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors. Results We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes. Conclusions The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.

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“…More directly, studying female reproductive milestones in relation to glaucoma or glaucoma endophenotypes can further inform our understanding of the pathophysiology of disease. In a recent study using a bioinformatics pipeline to prioritize the many newly discovered IOP-associated genes, 59 estrogen-receptor signaling was a key modulator of several of these IOP-associated genes. These genetic associations further underscore the importance of better understanding the associations of female reproductive milestones with glaucoma and IOP.…”

Section: Discussionmentioning

confidence: 99%