Molecular Underpinnings of Retinal Traits 1 Shared with Major Psychiatric Disorders
- 1Centre for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway
Abstract
Recent large-scale studies have enabled new knowledge about genetic underpinnings of morphological and electrophysiological alterations of the retina. Variation in retinal traits, often of neurodevelopmental origin, have been linked to major psychiatric disorders (MPDs). Here, we investigate the genetic overlap between MPDs and key retinal traits to identify underlying molecular mechanisms. We obtained genome-wide associations studies data for bipolar disorder (BD), major depression (MD), schizophrenia (SCZ), and the retinal traits retinal nerve fibre layer thickness (RNFL), ganglion cell inner plexiform layer thickness (GCIPL), and vertical cup-disc ratio (VCDR). We estimated the number of trait-influencing variants shared between traits with MiXeR and identified shared genetic loci with condFDR. Subsequently, we examined the biological pathways of the genes mapped to shared loci. This revealed that GCIPL shared the most genetic variants with MPDs ([~]60%), followed by RNFL ([~]40%), and VCDR ([~]20%). The genetic variants shared between retinal traits and MPDs showed disorder-specific patterns with more pronounced overlaps of SCZ and BD with RNFL, and MD negatively correlated with GCIPL. Gene-pathway analysis highlighted the importance of GABAergic neurotransmission and a two-stage neurodevelopmental process in SCZ, whereas the role of mitochondria and a weaker developmental component were observed in BD. The results also implicated synaptic functioning and gene-expression processes in MD. Furthermore, polygenic analysis suggested that the genetic architecture of retinal traits can distinguish between MPDs. Our findings indicate shared genetic underpinnings between retinal traits and SCZ, BD, and MD, implicating altered neurodevelopment and neurotransmission underlying the retinal link to major psychiatric disorders.
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BibTeX
@misc{jaholkowski2026molecular,
title = {{Molecular Underpinnings of Retinal Traits 1 Shared with Major Psychiatric Disorders}},
author = {P. Jaholkowski and N. Parker and I. O. Sveen and E. D. Wistrom and V. Fominykh and A. Szabo and P. Parekh and O. Frei and O. B. Smeland and K. S. O'Connell and S. Djurovic and A. M. Dale and A. A. Shadrin and O. A. Andreassen},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361809},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361809v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Molecular Underpinnings of Retinal Traits 1 Shared with Major Psychiatric Disorders
AU - P. Jaholkowski
AU - N. Parker
AU - I. O. Sveen
AU - E. D. Wistrom
AU - V. Fominykh
AU - A. Szabo
AU - P. Parekh
AU - O. Frei
AU - O. B. Smeland
AU - K. S. O'Connell
AU - S. Djurovic
AU - A. M. Dale
AU - A. A. Shadrin
AU - O. A. Andreassen
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361809
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361809v1
AB - Recent large-scale studies have enabled new knowledge about genetic underpinnings of morphological and electrophysiological alterations of the retina. Variation in retinal traits, often of neurodevelopmental origin, have been linked to major psychiatric disorders (MPDs). Here, we investigate the genetic overlap between MPDs and key retinal traits to identify underlying molecular mechanisms. We obtained genome-wide associations studies data for bipolar disorder (BD), major depression (MD), schizophrenia (SCZ), and the retinal traits retinal nerve fibre layer thickness (RNFL), ganglion cell inner plexiform layer thickness (GCIPL), and vertical cup-disc ratio (VCDR). We estimated the number of trait-influencing variants shared between traits with MiXeR and identified shared genetic loci with condFDR. Subsequently, we examined the biological pathways of the genes mapped to shared loci. This revealed that GCIPL shared the most genetic variants with MPDs ([~]60%), followed by RNFL ([~]40%), and VCDR ([~]20%). The genetic variants shared between retinal traits and MPDs showed disorder-specific patterns with more pronounced overlaps of SCZ and BD with RNFL, and MD negatively correlated with GCIPL. Gene-pathway analysis highlighted the importance of GABAergic neurotransmission and a two-stage neurodevelopmental process in SCZ, whereas the role of mitochondria and a weaker developmental component were observed in BD. The results also implicated synaptic functioning and gene-expression processes in MD. Furthermore, polygenic analysis suggested that the genetic architecture of retinal traits can distinguish between MPDs. Our findings indicate shared genetic underpinnings between retinal traits and SCZ, BD, and MD, implicating altered neurodevelopment and neurotransmission underlying the retinal link to major psychiatric disorders.
ER -