Recent studies suggest that there are at least 28 risk factors for Parkinson’s disease (PD) in 24 loci across the human genome,1 and additional genes cause PD or Parkinsonian syndromes in an autosomal dominant, autosomal recessive or X-linked manner.2 Moreover, the contribution of hereditary factors for PD development is probably more than 30%, emphasizing the importance of genetic factors in PD pathogenesis.3, 4 However, when reading the recent literature on PD genetics and its potential mechanisms, it seems that, although the genes and risk factors that cause PD or increase the risk for PD are being extensively studied, not enough attention is being given to protective genetic factors. Of course, for each genetic loci increasing PD risk there is its opposite, a protective one. For example, carriers of GBA mutations are at increased risk for PD; therefore, non-carriers are at decreased risk as compared with carriers. Yet, these non-carriers have an average population-level risk for PD. However, there are genetic factors that significantly reduce the risk for PD below the average population risk. Studying these naturally occurring protective variations may prove useful for finding new therapeutic targets.

In their recent study, Pihlstrøm et al.5 analyzed the protective PARK16 region, which was initially identified in the Japanese population6 and was later replicated in other populations worldwide. Single nucleotide polymorphisms (SNPs) in this region were associated with reduced risk for PD, and a haplotype that includes functional SNPs7 in the 5′ UTR and promoter region of RAB7L1 (now officially termed RAB29) was previously associated with a 10-fold risk reduction for PD in the Ashkenazi-Jewish population.8 This is probably the strongest protective genetic factor found to date in PD. Similarly, Pihlstrøm et al. also identified a haplotype in the 5′ UTR of RAB7L1 with about twofold reduced risk for PD in the Scandinavian population. This haplotype included two of the three markers that were analyzed for haplotypes in the Ashkenazi-Jewish population, rs1572931 and rs947211,5, 8 which allows a partial comparison with the Ashkenazi-Jewish population (Table 1). Interestingly, a specific combination of markers of these two SNPs, T allele of rs1572931 and G allele of rs947211, which were part of the 10-fold protective haplotype among Ashkenazi-Jews, did not exist in the Scandinavian population, or had a frequency of <0.01. Of note, the T allele of rs1572931 was also a part of yet another, independent protective haplotype in the Ashkenazi-Jewish population, which was associated with about 25% reduced risk for PD.8 Among Scandinavians, it were the C allele of rs1572931 and the G allele of rs947211 that were part of the strongest protective haplotype (Table 1). These observations, together with results from other studies,1, 5, 7, 8, 9 suggest that there are several independent haplotypes around the RAB7L1 promoter associated with reduced risk for PD.

Table 1 rs1572931 and rs947211 in protective and increased risk haplotypes among Ashkenazi-Jews and in the Scandinavian population
Full size table

As coding variants in the genes within the PARK16 locus were not associated with PD among Scandinavians (although these results need to be confirmed in additional populations), it is likely that the effect of PARK16 is related to regulatory variants. The existence of several independent protective haplotypes around the RAB7L1 5′ UTR and promoter region, together with important functional studies linking RAB7L1 and the disease causing LRRK2 and VPS35 genes,7, 10 suggest that RAB7L1 is the culprit in the PARK16 locus. Moreover, these data may suggest that any variation that affects the expression or splicing of RAB7L1 can influence PD risk. It is therefore imperative to further study the PARK16/RAB7L1 region in depth, and understand all of the genetic and epigenetic factors in both coding and regulatory regions that convey protection from PD.

Basically, PARK16 is just one out of several protective genetic regions and genes across the human genome that are associated with a reduced risk for PD, such as SCARB2, MAPT and others.1 Considerable effort is needed for studying these protective genes and their effects. Even if we do not fully understand the pathogenic mechanism leading to PD, by properly defining and perhaps manipulating these protective genetic factors we may find the long-awaited treatment for PD.