C. David Marsden Lecture Award
Accelerating and globalizing genetic discovery in Parkinson’s Disease
Andrew Singleton adds to his long history of genetic discoveries with a global effort that’s starting to yield far-reaching results.
How far have we come?
The last 30 years have witnessed incredible progress in understanding the genetic basis of Parkinson’s disease. Since the discovery of PD-causing mutations in the gene encoding α-synuclein in 1997, more than a dozen genes have been identified that contain mutations that confer high risk for PD. By and large these are each relatively rare, with the exception of the p.G2019S mutation in LRRK2. A substantial amount of progress has also been made in understanding the genetic basis of typical, apparently sporadic PD, with ~90 published independent risk variants identified, which individually confer risk that is small but collectively substantial.
Why should we continue?
Given so much has been found already, why should we continue? First, each new gene, each new locus, gives us more insight into the biology underlying disease. This is particularly relevant in the era of precision medicine, where we aim to match the therapeutic to the specific mechanism underlying disease in an individual. Notably, there is compelling data that clearly shows that genetic evidence underlying a therapeutic target is an important factor in predicting therapeutic success, and this holds true regardless of whether the effect size at the target is large or small. The bottom line, then, is that the more genetic information we can garner about the disease, the better chances we have of devising disease-altering therapies.
What’s left to do?
In Northern European ancestry populations, where we have identified about 1⁄3 of the known heritable component of PD, there remains much to be done; however, this pales in comparison to what is left to understand in populations outside of this group. Almost nothing is known about the genetic basis of disease in many major ancestral groups. If we believe understanding disease is an important step along the path of treating disease, it is essential that we understand disease in all ancestral groups. Moreover, it is an essential step if we are to realize the promise of precision medicine.
How do we get where we need to be?
Starting in 2020, myself and Cornelis Blauwendraat launched the Global Parkinson’s Genetics Program (GP2), supported by the Aligning Science Across Parkinson’s Initiative (ASAP) and in partnership with the Michael J. Fox Foundation for Parkinson’s Disease Research (MJFF). This program aims to dramatically expand our understanding of the genetic basis of disease, and to do so in all populations. Now supported through 2029 and expanded to include progressive supranuclear palsy, multiple system atrophy, corticobasal syndrome, and Lewy body dementia, GP2 will generate genetic findings in PD and these other diseases in more than 200,000 individuals from around the world. GP2 does this by growing a cohesive and functional worldwide research community. GP2 provides training opportunities, local capacity-building initiatives, and resources to enable the ascertainment and analysis of genetic data by the investigators embedded in the very populations they are studying. Moreover, GP2 aims to promote the next generation of worldwide leaders in PD research.
While still in its early days, GP2 is already making significant inroads and exciting findings. Most recently, the discovery of a major novel risk factor in individuals of West African ancestry is a striking example of the power and importance of diversifying genetics research. This discovery reveals a novel risk variant in GBA1, present in 50% of PD patients from Nigeria; highlights a new disease mechanism at this gene; and opens the potential for precision-based therapeutic trials targeting GBA1 in Africa. While this first finding is exciting, I believe this is just the first example of a large number of such findings from GP2 groups around the world.
With thanks to GP2 members, the thousands of patients and volunteers who take part in this work, and to the support of ASAP and MJFF, as well as my own institution, the National Institute on Aging.