Connecting ocular and systemic health: Phenome- and genome- wide analyses of retinal layer thicknesses from optical coherence tomography imaging across >50k participants

Abstract

Purpose : The human retina is a multi-layered tissue which offers a unique window into systemic health. Large-scale analyses of optical coherence tomography (OCT) imaging with phenotypic and genomic data offer the potential to identify novel retinal imaging biomarkers of health and biological pathways for retinal physiology.

Methods : We conducted phenome- and genome- wide analyses of 9 retinal layer thicknesses (GCC, RNFL, GCL, IPL, INL, OPL+ONL, PS, RPE+BM, CSI) using segmented Topcon OCT images across 44,823 UK Biobank participants, with replication in the LIFE-Adult Study (N=6,313). Phenome-wide analyses associated layer thickness with 1,866 incident ICD-based conditions (over 10-year follow-up) and 88 quantitative traits, after adjusting for age, sex, smoking, height, weight, and spherical equivalent. Genome-wide analyses (GWAS) were performed to identify inherited loci and linked to retinal layer thicknesses.

Results : Mean age was 56 (SD 8 years), 55% were female, and 56% were never-smokers. Significant associations (P<3x10^-5) were detected between each standard deviation of retinal layer thinning and hazard ratio for development of future ocular (RNFL-glaucoma 1.77; PS-AMD 1.39), neuropsychiatric (GCL-multiple sclerosis 2.87, epilepsy 1.55; PS-schizophrenia 1.90), cardiac (PS-myocardial infarction 1.17, hypertension 1.09; CSI-hypertrophic cardiomyopathy 2.05), metabolic (PS-Type 2 diabetes 1.28, diabetic polyneuropathy 1.67), and pulmonary disease (PS-COPD 1.31, chronic bronchitis 1.52), as well as end-organ failure (PS-respiratory failure 1.46, heart failure 1.21, NASH 1.53), and mortality (PS-1.16; GCC-1.12). GWAS identified 259 loci acting through diverse biological pathways. Consistent epidemiological and genetic analyses suggested a link between thinner RNFL and glaucoma, PS and AMD, as well as poor cardiometabolic and pulmonary traits (elevated BMI, body fat, creatinine, heart rate, lower cardiac ejection fraction, poor pulmonary function tests) with thinner PS, elevated blood pressure with thinner RNFL and CSI, and elevated HDL cholesterol with thinner RPE+BM.

Conclusions : We identified multiple inherited genetic loci and acquired cardio-metabolic-pulmonary conditions associated with thinner retinal layers, and retinal layers wherein thinning is predictive of future ocular and systemic conditions.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Study Schematic

 

GWAS