The Dark Genome in Parkinson’s Disease
Arguably, one of the biggest paradigm shifts in understanding Parkinson disease (PD) was the discovery, in the late 1990’s and in the first decade of the 2000’s, of genes that cause familial forms of PD or that increase the risk of PD. These genes, most of which are known to the readership of this blog and include SNCA, PKRN, PINK1, DJ-1, LRRK2 and GBA1, have been intensely studies and have provided exciting and justifiably rational - because based on human genetics - new targets for PD therapy. However, over the past decade since these initial discoveries, advances in human genetics and in particular genome-wide association studies (GWAS) have uncovered nearly a hundred additional genetic risk loci associated with PD. This provides a tremendous opportunity to better understand how PD develops and possibly even target therapies based on individuals’ particular genetic makeup. However, the discovery rate of these new genes has been so fast that it has far outpaced our progress in understanding their roles in PD. Indeed, much of the research community has continued to focus on the first 5-6 “popular” PD genes, some discovered over 20 years ago, while many of the newer ones remain understudied. I will refer to this set of under-explored genes as the “PD Dark Genome”.
I’d like to explain why our progress in understanding the Dark Genome in PD has been comparatively slow and discuss why, despite the challenges, I think it is important to prioritize this line of research. GWAS’ reveal the locations (typically called loci) in the genome where variants in the sequence of individuals’ DNA are associated with an increased risk of developing PD. The variants often manifest themselves as changes in a single DNA base pair, referred to as single-nucleotide polymorphisms (SNPs). The sum of all the PD risk SNPs for a given individual can be expressed in terms of a polygenic risk score, which reflects their cumulative genetic risk of developing PD. So why has it been so difficult to study the genes identified by GWAS?
First, most SNPs occur outside of protein-coding regions of genes and thereby do not affect the integrity of the proteins that the PD genes encode. Instead, it is believed that the major effect of PD risk SNPs is to change the expression levels of the respective gene or its epigenetic regulation. This makes studying the effects of PD risk SNPs in model systems extremely challenging because, in addition to being subtle, the effects may be cell-type or tissue specific. Despite their subtle effects and the relatively small risk of developing PD conferred by each individual SNP, cumulatively their effects are likely to be important and the genes that drive the risk are likely to reveal important cellular pathways in PD pathogenesis.
Which brings me to the second challenge we face in understanding the Dark Genome in PD. Most PD GWAS loci are defined not by one but by a cluster of SNPs that significantly affect PD risk. In the genetic interval surrounding these SNPs, there lie not one but several genes. While it is often assumed that the gene closest to the most significant SNP(s) is the culprit “PD gene”, this may not necessarily be the case as it is well know that DNA variants may have long-range effect on genes that are far away from the actual SNP. It is estimated that the genetic intervals of the roughly 80 loci identified in the two latest PD GWAS’ contains more than 400 genes. So far, beyond just choosing the nearest gene, we have relied mostly on statistical or bio-informatics approaches to come up with best-guesses to nominate a gene within a given locus. While these have been helpful, more definitive and broadly applicable functional approaches to nominate PD genes in each locus are still lacking.
While the complexities and challenges involved in studying the Dark Genome in PD may seem daunting, it is a challenge we must meet. Identifying which gene at each GWAS locus is responsible for PD risk, characterizing their respective role in PD and understanding how they work together in pathways will provide a more complete picture of the genetic architecture underpinning PD and more holistic models of disease mechanisms. Moreover, while the absolute risk conferred by each of these GWAS PD genes may be relatively small, they may point to new target for therapy.Indeed, just as academic scientists have focused most of their efforts on a few of the early PD genes, the pharmaceutical industry has been targeting the same popular genes for drug development, often over and over, in competition with each other and without any successes to show for it. One reason is that given the complexities described above, the lack of reliable tools and models available to study these genes and the high cost of drug development, Pharma considers it too risky to invest in making drugs against theses lesser-studied genes. Yet, with the advent of technologies such as CRISPR/Cas9 gene editing and induced pluripotent stem cells (iPSC) technologies allowing us to differentiate patient-derived cells into different types of brain cells, the time is ripe to develop a comprehensive strategy to systematically develop and openly distribute tools and models (cell lines, antibodies, chemical probes) to functionally disentangle how these lesser-studied genes contribute to PD. However, the scope and scale of such an initiative is beyond the capacity of any single lab or even a single research center or organization. This is why, as a community, we need to pull together to drive a system change to collectively “de-risk” the Dark Genome in PD in order to better understand how PD develops and to identify new targets for therapy for patients with PD.
Edward A. Fon, MD, FRCP(C) is the Scientific Director, Montreal Neurological Institute-Hospital Canada and Research Chair in Parkinson’s Disease Professor of Neurology and Neurosurgery McGill University. He will be speaking at the WPC 2023 Congress in Barcelona. View the Scientific Program here.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®