The role of genetics in PD continues to be a major focus in the field and much of what we know about possible underlying mechanisms of PD cause and pathogenesis has come through studies of genes (e.g., alpha-synuclein) that have been linked to the disease through studies of families with a history of the disease. However, the role of genetics in the larger population of more sporadic PD remains unclear. Many genes have been implicated in small-scale studies as contributing potential risk for PD, but often these studies do not replicate when tested independently in additional populations.
In 2003, MJFF funded a large-scale study through its LEAPS mechanism to survey the entire human genome for single-nucleotide polymorphisms (SNPs; single-letter changes in the DNA sequence that contributes to the normal and abnormal variations seen between individuals and groups of individuals) that may be associated with greater risk for PD. The study was led by Drs. Jim Maraganore (Mayo Clinic) and David Cox (Perlegen Sciences), who collected DNA samples from 443 pairs of siblings discordant for PD, as well as 332 pairs of unrelated PD-affected and healthy individuals. The sibling pair samples were tested (genotyped) for approximately 250,000 SNPs and approximately 1800 of these which demonstrated statistical association to PD in the first group were further genotyped in the second set of unrelated pairs. Final analysis identified 13 SNPs that maintained statistical association (in the same direction of effect) in both population “tiers”, although the overall contribution of any single SNP was low, suggesting that no single common genetic variation could explain a large percentage of PD risk in these individuals.
In order to better understand these findings and to provide further clarity for the field, MJFF funded a SNP validation study of the top 13 SNPs highlighted by Dr. Maraganore to determine if these associations held within a much larger population of people. To do this, MJFF coordinated investigators from those partaking in the MJFF Edmond J Safra Global Genetics Consortia program (a program that brought together collaborative teams of investigators to tackle critical questions in the PD genetics field). In total, the teams contributed over 12,000 DNA samples from unrelated PD-affected and healthy individuals collected from multiple international sites. These samples were genotyped for the 13 SNPs and analyzed using sophisticated statistical approaches. Results of this analysis did not confirm that the 13 SNPs identified by Dr. Maraganore are associated with greater PD risk in this larger population. (In addition, several smaller independent studies not funded by MJFF also were generally unable to confirm the original Maraganore findings.) The results of this study have been published by Lancet Neurology and are now available online.
Although disappointing, the lack of replication of these findings does not mean that genetics play no role in sporadic PD. Rather, it means that no single common variation in our DNA can explain a large percentage of PD risk in the population. This conclusion is also supported by a second genome-wide SNP association study being published coincident to our own (Singleton et al., Lancet Neurology) which looked at almost twice as many SNPs as Dr. Maraganore, but also found no single SNP that contributed greatly to PD risk. However, as researchers begin to sift through both of these large datasets and apply more sophisticated analyses it is possible that more complex interactions involving multiple SNPs (perhaps in combination with environmental factors) will be revealed to contribute greatly to PD risk. Both of these large datasets will be available online so that researchers can mine these data for further insight in the underlying genetics of PD.