As an anatomical extension of the brain, the retina of the eye is synaptically connected to the visual cortex, establishing physiological connections between the eye and the brain. Despite the unique opportunity retinal structures offer for assessing brain disorders, less is known about their relationship to brain structure and function. Here we present a systematic cross-organ genetic architecture analysis of eye-brain connections using retina and brain imaging endophenotypes. Novel phenotypic and genetic links were identified between retinal imaging biomarkers and brain structure and function measures derived from multimodal magnetic resonance imaging (MRI), many of which were involved in the visual pathways, including the primary visual cortex. In 65 genomic regions, retinal imaging biomarkers shared genetic influences with brain diseases and complex traits, 18 showing more genetic overlaps with brain MRI traits. Mendelian randomization suggests that retinal structures have bidirectional genetic causal links with neurological and neuropsychiatric disorders, such as Alzheimer's disease. Overall, cross-organ imaging genetics reveals a genetic basis for eye-brain connections, suggesting that the retinal images can elucidate genetic risk factors for brain disorders and disease-related changes in intracranial structure and function.

The authors have declared no competing interest.

The study has been partially supported by start-up funds from Purdue Statistics Department and funding from Analytics at Wharton.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The individual-level data used in the present study have been openly available from the UK Biobank (https://www.ukbiobank.ac.uk/) study.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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GWAS summary statistics of brain MRI traits can be freely downloaded at BIG-KP (https://bigkp.org/). GWAS summary statistics of retinal imaging traits will be made publicly available at Eye-KP (https://www.eyekp.org/). The individual-level data used in this study can be obtained from https://www.ukbiobank.ac.uk/.

https://bigkp.org/

https://www.eyekp.org/