WEHI Special Genetics and Gene Regulation Seminar hosted by Professor Melanie Bahlo

Roberto Bonelli, PhD

Principal Scientist- Lowy Medical Research Institute, USA

 

Integration between large phenomics and genomics data using scRNA-seq techniques reveal genetically driven differential progression patterns in neurodegenerative eye disease
 

L3C Seminar Room

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Including Q&A session

We present a study based on clinical imaging phenotypic data from a large biobank of eyes affected by Macular Telangiectasia Type 2 (MacTel). We extracted 96 clinically graded phenotypic variables on 7,328 eyes (3,675 patients), 15% of eyes had longitudinal observations with an average of 5 years. By borrowing techniques from single-cell RNA-seq analysis, we were able to divide the eyes of MacTel patients into 13 distinct clusters. Just like cell differentiation, these clusters were differentiated by retinal phenotypes’ presence and severity. Pseudo-time calculations revealed a clear severity difference between these clusters, validated via a clinically defined linear severity score. Minimum spanning tree calculation (oblivious to the longitudinal nature of some of our data) revealed two differential progression routes across clusters, one leading to a more vascular-altered retina while the other leading to a neurodegenerative process resulting in vision loss. The longitudinal data additionally validated this bifurcated route. Analysis of the progression route in fellow eyes revealed a strong intra-patient agreement. Integration with demographic data revealed that patients affected by type 2 diabetes – a known MacTel comorbidity – were significantly more likely to progress following the neurodegenerative route. By integrating genetic data on 2,182 patients, we tested for association between all MacTel significant GWAS loci and progression routes and found a strong genetic association with a locus known to impact retinal vasculature and thickness. Lastly, modelling the genetic loci effect on clinical phenotypes revealed a strong genetic background on retinal insult presence, severity, and progression rate.

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