Reflections From ONDRI’s Genomics Platform

Nov 19, 2021 | Blog, Science Simplified

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We are born with our genes; and for the most part, they do not change throughout our life. Genes play a very important part in our bodies’ development. They are responsible for producing mRNA and proteins. mRNA functions as a messenger, telling cells how to make proteins. Proteins are a main component of our cells, giving our tissues and organs their shape and facilitating their functions.

When proteins cannot do their job, the body cannot function properly. And it all starts with the genes.

“Our genetic variation helps explain the differences between us, our eye colour, our height, and perhaps, whether or not we have a disease”, said Allison Dilliott Ph.D., formerly a student at Western University’s department of biochemistry, currently a post-doc at McGill University.

“What makes studying neurodegenerative disease so challenging is that, to a large extent, the symptoms associated with neurodegeneration show up quite late in life. The variants causing some of these symptoms live within the body from birth; they create some disturbance, but typically not enough to be noticeable as symptoms. And then, one day these disturbances become symptoms, and it’s often too late to do anything about it,” she continues.

Explaining gene variants

Our genes are usually “normal”¹, but sometimes the genetic code may contain variants or mutations; variants are differences in the DNA sequence compared to the “norm”. Fortunately, most variants cause no discernable impact to the body. But a few may cause detectable disturbances that range from minimal to significant, including association with various disorders and diseases. In general, the rarer a variant, the more severe its potential impacts.

Genomics research at ONDRI has largely focused on trying to find early markers of neurodegeneration.

Researchers in ONDRI’s genomics platform helped to set up the protocol for the Foundational Study. They have also been poring over the study data over the past several years.

What are the main findings to date?

In a nutshell, there is a lot more genetic overlap between the neurodegenerative diseases studied by ONDRI than what has been reported previously. These diseases are very heterogenous, no two people are affected in exactly the same way; and the genetic underpinnings of these diseases are still incompletely understood.

In studying the Foundational Study data, the ONDRI genomics group has come up with some truly novel findings and other observations:

1. 1. 1. The relationship between rare variants in the NOTCH3 gene and features of cerebrovascular (blood vessel) diseases in Parkinson’s disease patients
      - NOTCH3 variants are typically associated with CADASIL, a rare disorder of small blood vessels in the brain
      - The rate of NOTCH3 gene rare variants in the ONDRI Parkinson’s disease cohort was higher than expected, indicating a potential overlap between these diseases and a possible new lead towards treatments for Parkinson’s disease
    2. The relationship between APOE and cognition across neurodegenerative diseases
      - APOE E4, a frequent variant of the APOE gene, is typically associated with Alzheimer’s disease
        
        This variant was observed in some other ONDRI study disease cohorts
        
        The APOE E4 variant appears to influence cognition no matter the neurodegenerative diagnosis
    3. The unique study design of ONDRI, in which the same protocols are followed across various diseases, is leading to a deeper understanding of the genetic fingerprints of these diseases and their potential shared genetic overlap
    4. While the hunt is on for new genes associated with neurodegenerative disease, there is still a lot to learn about how the genes with a known role in neurodegeneration function and interact

“The ONDRI study has generated deep, rich, multi-modal data on each participant, which makes it very attractive for studying new ideas and generating novel conclusions”, said Dilliott.

She continues: “Doing this work has made me question why many previous studies have grouped people based on clinical diagnosis, while underneath they have something in common in their genes.”

We have to think outside the box and be less siloed in our approach in this field. There is so much overlap between these diseases and we should think about this work in a new way. ONDRI has allowed us to do that.

As technology and tools progress, ONDRI has added a new Molecular/Neuropathology platform to complement the Genomics platform, arming researchers with more ways to help solve the complexity behind neurodegenerative diseases and dementia. More to come in this area.