By Dr. Luca Marsili
The availability of cost-effective genetic sequencing over the last 20 years has led to an explosion of data about the genetic basis of neurodegenerative diseases. A large number of genetic mutations have been implicated in causing a form of Parkinson’s disease or other Parkinsonisms. The next decade promises the discovery of many more genes to that catalogue thanks to programs like ASAP’s GP2 and the Parkinson’s Foundation’s PD GENEration, especially if a recent pre-print claiming that we can now sequence genomes for just $15 in a mere 12 hours turns out to be true and the process reproducible everywhere. Yet the question remains, what are patients and their doctors supposed to do with all that information?
The past two decades of discoveries have revealed more and more genetic mutations but instead of being major drivers in unleashing the disease, they yield smaller effects, increasing the risk of Parkinson’s without being prescriptive. While some of the early genetic discoveries were found to exert significant effects among carriers of those mutations in rare (e.g., SNCA) or slightly more common patient populations (e.g., GBA, LRRK2, PRKN), recent discoveries have been of genes whose mutations have smaller roles and in fewer individuals (e.g., ATP13A2, SYNJ1).
Further confusing the picture, carriers of the same mutation often have quite different clinical outcomes. For example, patients carrying LRRK2 mutations can go on to develop a relatively benign form of Parkinsonism, or much more aggressive diseases like dementia with Lewy bodies or multiple system atrophy; yet others never develop any kind of neurodegenerative disease. A similar story comes from the C9ORF72 gene where families may have one child who goes on to develop amyotrophic lateral sclerosis (ALS) and the other frontotemporal dementia, very different diseases as currently conceived, at least. These indicate that there are many more factors involved that just our genome, and that genetic variability cuts across our clinically defined boundaries of disease and can play a role in a variety of different forms of neurodegeneration.
Despite the addition of all these above-mentioned genes to our lists of “Parkinson’s disease” genes, the majority of cases of Parkinson’s remains unexplained. This leads us to conclude that something is missing from our approach to genetics. Except for a small minority of cases, genetic markers alone will not suffice to match patients to disease modifying therapies. Thus, the genetics of patients with neurodegenerative diseases must be studied in the context of other elements of human biology applicable to the same individuals, using a wide source of analytical techniques (e.g., transcriptomics, proteomics, metabolomics, epigenomic, and microbiomics, each of which will be discussed in future blog posts), to enable us to identify the appropriate therapy for each individual.
Therefore what we need is broad population-based studies of aging like the CCBP. Over the next decade we will conduct an extensive DNA sequencing of each of our five thousand participants. We will then combine that information with the data we get from the other biological datasets mentioned above to help us understand which pathways are most relevant to each person’s particular disease. This will then enable us to match patients with biologically-defined disorders to therapies suited to alter such abnormal biology, increasing the chance of modifying the course of an individual’s disease. This is both the challenge and the promise of precision medicine applied to patients with neurodegenerative disorders.
Genetics in the first two decades of the 21st century has helped guide many of our attempts to develop new treatments for neurodegenerative diseases. But to truly realize the potential that the genomic revolution promised we must take the next step and start integrating and individualizing that information with everything else we are learning about the biology of aging to disentangle how incredibly complex genetic and molecular pathways unfold in each affected person to better treat each one.