Macular structural integrity estimates are associated with Parkinson's disease genetic risk

Abstract

Background: Optical coherence tomography (OCT) is a non-invasive technique to measure retinal layer thickness, providing insights into retinal ganglion cell integrity. Studies have shown reduced retinal nerve fibre layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness in Parkinson's disease (PD) patients. However, it is unclear if there is a common genetic overlap between the macula and peripapillary estimates with PD and if the genetic risk of PD is associated with changes in ganglion cell integrity estimates in young adults.

Method: Western Australian young adults underwent OCT imaging. Their pRNFL, GCIPL, and overall retinal thicknesses were recorded, as well as their longitudinal changes between ages 20 and 28. Polygenic risk scores (PRS) were estimated for each participant based on genome-wide summary data from the largest PD genome-wide association study conducted to date. We further evaluated whether PD PRS was associated with changes in thickness at a younger age. To evaluate the overlap between retinal integrity estimates and PD, we annotated and prioritised genes using mBAT-combo and performed colocalisation through the GWAS pairwise method and HyPrColoc. We used a multi-omic approach and single-cell expression data of the retina and brain through a Mendelian randomisation framework to evaluate the most likely causal genes. Genes prioritised were analysed for missense variants that could have a pathogenic effect using AlphaMissense.

Results: We found a significant association between the Parkinson's disease polygenic risk score (PD PRS) and changes in retinal thickness in the macula of young adults assessed at 20 and 28 years of age. Gene-based analysis identified 27 genes common to PD and retinal integrity, with a notable region on chromosome 17. Expression analyses highlighted NSF, CRHR1, and KANSL1 as potential causal genes shared between PD and ganglion cell integrity measures. CRHR1 showed consistent results across multiple omics levels.

Interpretation: Our findings suggest that retinal measurements, particularly in young adults, could be a potential marker for PD risk, indicating a genetic overlap between retinal structural integrity and PD. The study highlights specific genes and loci, mainly on chromosome 17, as potential shared etiological factors for PD and retinal changes. Our results highlight the importance of further longitudinal studies to validate retinal structural metrics as early indicators of PD predisposition.

Keywords: CRHR1; KANSL1; NSF; Ganglion cell; Genetics; Parkinson’s disease; Retina.

Fig. 1

Spectral Domain optical coherence tomography scans centred on the disc (left) and macular (right). The 3.5 mm-diametre disc-centred B-scan obtains measurements of the peripapillary retinal nerve fibre layer thickness. The 31-slice macular-centred scans cover a 6-mm diameter area

Fig. 2

(A) Polygenic risk scoring analysis in the Raine Study (Gen2), which included two time point measurements (20 and 28 years of age) and longitudinal changes of three OCT outcome variables: GCIPL, pRNFL, and overall macular thickness. (B) Study design to evaluate the genetic overlap between ganglion-cell structural estimates (i.e., macula RNFL and GCIPL) and Parkinson’s disease

Fig. 3

The phenotypic variance explained (R²) by the Parkinson’s disease polygenic risk score for changes in retinal thickness from 20 to 28 years of age. The macular grid of the GCIPL layer is reported. Subfields are described as inferior (I), nasal (N), superior (S), temporal (T), inner (1), and outer (2)