Implicating Causal Brain Magnetic Resonance Imaging in Glaucoma Using Mendelian Randomization

Abstract

BackgroundGlaucoma is hypothesized to originate in the brain but manifests as an eye disease as it possesses the common features of neurodegeneration diseases. But there is no evidence to demonstrate the primary brain changes in glaucoma patients. In the present study, we have used Mendelian randomization (MR) to understand the causal effect of brain alterations on glaucoma.MethodsOur MR study was carried out using summary statistics from genome-wide associations for 110 diffusion tensor imaging (DTI) measurements of white matter (WM) tracts (17,706 individuals), 101 brain region-of-interest (ROI) volumes (19,629 individuals), and glaucoma (8,591 cases, 210,201 control subjects). The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method and verified by two other MR methods, including MR Egger, weighted median, and extensive sensitivity analyses.ResultsGenetic liability to fornix fractional anisotropy (FX.FA) (OR = 0.71, 95%CI = 0.56–0.88, P = 2.44 × 10–3), and uncinate fasciculus UNC.FA (OR = 0.65, 95%CI = 0.48–0.88, P = 5.57 × 10–3) was associated with a low risk of glaucoma. Besides, the right ventral diencephalon (OR = 1.72, 95%CI = 1.17–2.52, P = 5.64 × 10–3) and brain stem (OR = 1.35, 95%CI = 1.08–1.69, P = 8.94 × 10–3) were associated with the increased risk of glaucoma. No heterogeneity and pleiotropy were detected.ConclusionOur study suggests that the fornix and uncinate fasciculus degenerations and injures of the right ventral diencephalon and brain stem potentially increase the occurrence of glaucoma and reveal the existence of the brain-eye axis.

Ankylosing spondylitis and glaucoma in European population: A Mendelian randomization study

“…Furthermore, POAG (3,412 cases and 210,201 controls) and PACG (588 cases and 210,201 controls) were included as histological subgroups for further comprehension of the causality between genetically predisposed AS and glaucoma subtypes. This study defines glaucoma by H40-H42 of the International Classification of Disease-10, and other studies have supported the use and accuracy of the International Classification of Disease coding for this diagnosis ( 28 , 29 ) ( Figure 1 ).…”

“…In order to avoid the inclusion of data from the same participant, the Data of Genetic Instruments for glaucoma was selected from the FinnGen consortium, with a total of 218,792 individuals of European ancestry (including 8,591 glaucoma cases and 210,201 controls) ( 28 ). Furthermore, POAG (3,412 cases and 210,201 controls) and PACG (588 cases and 210,201 controls) were included as histological subgroups for further comprehension of the causality between genetically predisposed AS and glaucoma subtypes.…”

Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study

“…To date, the use of MR approaches in the context of POAG has been relatively limited. Despite this, these methods have been successfully implemented to explore the relationship between POAG and a small number of traits including brain alterations 11 , plasma lipid levels 12 , fatty acids 13 , type 2 diabetes 14 , HbA1c levels 14 , fasting glucose, coffee consumption 15 and blood pressure 16 .…”

Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study

“…small number of traits including brain alterations 11 , plasma lipid levels 12 , fatty acids 13 , type 2 diabetes 14 , HbA1c levels 14 , fasting glucose, coffee consumption 15 and blood pressure 16 .…”