Genetics. It’s Complicated. And Awesome.
Parkinson’s is a genetic disease. But it’s a bit more complicated than that. Here I’m going to try to briefly discuss some of the key issues in Parkinson’s genetics.
How genetic is Parkinson’s disease?
This is a common question and one we can use genetics to answer, at least approximately. What the data tells us is that for an average person with Parkinson’s, approximately 25% of the reason they have disease is due to common inherited genetic influences. For some people it will be more, for others less, but that is the average. This is only an estimate, and likely an underestimate (it doesn’t account for certain types of genetic variation), however, it’s a good place to start. So, this leads us to some questions, how much of that genetic risk have we found so far (about ⅓), can we find the remainder (yes), and what else effects our risk for disease? For this last question - there are two broad categories that are often suggested - the environment (or everything that happens to us) and random molecular events. Tackling these two issues is too much for this blog - but it is worth addressing the question: If there is so much that is not genetic, why focus on genetics?
Why Genetics?
What, really, is the point? Genetics, in many ways, is the beginning, an understanding of genetic influences in disease is really the foundation of knowledge about how that disease is initiated, how our body reacts to the disease process, and how it progresses. At the most basic level it provides us with a list of the key players (genes) in the disease - we then use that list of players to work out the molecular and cellular mechanisms that, at their essence, are the disease. In understanding mechanism, we can then work to understand how to halt, reverse, or slow that mechanism. This, in many ways, is the basis of modern disease research. Increasingly, genetics is also being used to try and understand other facets of disease - we’re not there yet, but it has the potential to give us insight into whether Parkinson’s is really one disease, or whether there are different underlying mechanisms in different individuals, it also holds promise in helping to predict disease - who will get it, when will they get it, and what will the disease course be like. It’s important to note - we’re not there yet, and it is very unlikely that genetics will be able to enable these things by itself - incorporating other technologies, data, and advances will be key. However, all of this is aimed toward developing the right therapeutics, for the right patients, and applying them at the right time. There is no cure yet, so we cannot declare victory for this approach, but it is informative that therapies against genetic-based targets such as alpha-synuclein, Lrrk2, and GBA, are currently being tested in clinical trials.
Where were we?
We were of the opinion, for a long time, that Parkinson’s wasn’t genetic. This view changed around 25 years ago. The discovery of Parkinson’s disease-causing mutations in the gene that encodes the protein alpha-synuclein occurred in 1997 and changed the field overnight. An immediate concern was that, because such disease-causing mutations were rare and often associated with unusual forms of disease, that they were not relevant to typical Parkinson’s disease. This concern was almost immediately answered with the observation that the alpha-synuclein protein is a major component of Lewy bodies - the hallmark pathology of all Parkinson’s disease cases. So, mutations in the gene encoding alpha-synuclein are a very rare cause of disease - but this protein is a key component of disease in every Parkinson’s case, regardless of cause. This immediately placed alpha-synuclein central in the disease process, but it also showed elegantly that rare genetic forms of Parkinson’s disease are informative for the typical form of disease. From that point the hunt for disease causing mutations was on - and there followed a series of successes with new genes that contain disease causing mutations being identified such as: parkin, pink1, dj1, lrrk2, vps35, vps13c, to name a few.
Where are we?
With the exception of Lrrk2, most genes that contain Parkinson’s disease-causing mutations are rare causes of disease. Lrrk2 mutations are responsible for disease in ~2% of North American cases, but many more in certain populations. So what about other types of genetic influence? In ~2005 our research shifted to include examining how common variability in the human genome might influence disease. Variants in our genetic code that we each carry and that many of us have in common. Technological advances really made it possible for us to look at these changes at scale, and afforded a great deal of work on the “common disease, common variant” hypothesis. Put simply, this states that rather than a single really influential and rare variant, many diseases are caused by the combined influence of many common variants in the genome each of which is of small effect but that collectively have a significant impact. Thus, many of us in the field started to focus our energies not just on discovering rare causes of disease in small families but also on looking at millions of common genetic changes in tens of thousands of patients. This has led us to the identification of almost 100 different regions in the human genome that we know contain variants that impart risk for disease, each individually small, but collectively substantial.
Where are we going?
We’ve come a long way for sure, a large number of disease-causing mutations, and a larger number of risk variants have been identified - but there is certainly much left to learn. We know there is a great deal of genetic influence left to map and understand and an exciting array of new tools and approaches which mean that questions we couldn’t address even a year or two ago are now answerable. I see great progress in lots of areas, understanding disease mechanisms, improving risk predictions, providing insights into disease course, defining new therapeutic targets. The efficiency and speed with which we can do this work will only improve and this is incredibly exciting. I also see some urgent unmet needs. One, most prominent, is in the genetic dissection of disease in diverse populations. Parkinson’s genetic investigation has been performed mainly in patients of Northern European ancestry, these individuals represent a minority of the world population. We have to broaden our understanding. Parkinson’s disease is a World challenge, and we must understand disease in World populations in order to be able to meet that challenge. Thus, accelerating our discovery work, and making it more globally relevant are two key areas that we are focusing on in the new initiative, the Global Parkinson’s Genetics Program over the next few years.
So indeed, its complicated, but Parkinson’s is a genetic disease and this very fact will be the basis for the field’s successful development and application of treatments for this disease. Treatments that will be more precise than in the past, based on these future genetic findings, which makes for an exciting few years ahead.
Andrew Singleton, PhD is a Program Co-chair for the WPC 2023 and has spoken at past World Parkinson Congresses. He is the director of the Center for Alzheimer’s and related dementias at National Institute on Aging, NIH.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®