Parkinson’s Disease (PD) is a well-known, complex disorder brought about by a mix of polygenic and environmental factors.
Around 1-2% of PD cases are caused by a single gene. Multiple genes have been identified to give rise to PD or Parkinsonism by means of either autosomal dominant or autosomal recessive inheritance patterns. A 2004 study established that mutations in PINK1 (PARK6) caused autosomal recessive early-onset PD, and in the past ten years many studies have indicated that carrying a single heterozygous PINK1 mutation is linked with higher risk for PD.
Presently, a well-known cause of early-onset PD is homozygous or compound heterozygous mutations in PINK1 that bring about loss of function. Interestingly, several studies have also indicated a possible function for heterozygous PINK1 mutations on Parkinsonism in offspring of biallelic mutation carriers, or PD in possible families with an apparently autosomal dominant pattern of inheritance for PINK1, particularly for PINK p.G411S. This possible effect is backed up by functional evidence which shows that the PINK p.G411S mutation interferes with the protective functions of PINK-mediated mitochondrial quality control. Additionally, PINK1 p.G411S heterozygous carriers appear to exhibit a significant reduction in kinase activity. However, there is a lack of replication in large data sets presenting a robust genetic association for heterozygous PINK1 variants and PD susceptibility. This study thoroughly examines the effect of heterozygous PINK1 variants, including p.G411S, in PD susceptibility with the use of large data sets; a total of 376,558 participants which included 13,708 PD cases and 362, 850 controls.
Genotyping data and exome sequencing and resequencing data were acquired through the UK biobank data, McGill University and International Parkinson’s Disease Genomics Consortium (IPDGC) members, collaborators, and public resources. The presence of PINK1 variants were assessed in both control and PD samples; this was achieved through annotating the entire PINK1 region using ANNOVAR, and filtering for loss-of-function variants (stop-gain, frameshift insertion and frameshift deletion) and potential pathogenic variants based on ClinVar.
A total of 177 coding (missense or loss-of-function) variants in the coding region of PINK1 were identified. Of these 177 variants, 6 were previously classed as pathogenic based on ClinVar and a further 13 could be classed as pathogenic because of clear loss of function, therefore giving a sum of 19 identified pathogenic variants. A further 11 variants were classed as of uncertain significance based on ClinVar. No one was identified carrying 2 pathogenic variants.
From the IPDGC and McGill data sets, the study assessed 12,166 cases and 12,489 controls for their PINK1 p.G411S status. It was found that 57 were heterozygous carriers, 24 cases and 33 controls. No homozygous carriers of PINK p.G411S participants were identified. Meta-analysis of the results showed a nonsignificant association between PINK1 p.G411S and pathogenicity. The UK biobank was used as an independent data set; 357 heterozygous carriers of the PINK1 p.G411S mutation were identified, which resulted in a similar frequency as the other data set. Overall, these frequencies again argue against pathogenicity. When analysing heterozygous pathogenic variants in PINK1, overall percentages of pathogenic variants 0.089% and 0.071% in cases and controls respectively, which indicated no clear differences.
Deleterious PINK1 variants are the second most common cause of autosomal recessive PD after mutations in PRKN (PARK2). Many studies reported that damaging variants found in heterozygous state could also contribute to PD development. In contrast to previous studies and reports, the results of this study suggest that the PINK1 p.G411S variant is likely benign and that other PINK1 pathogenic variants in heterozygous state are likely not linked with increased PD susceptibility.
In our current scientific and highly technology-based society where large-scale genotyping and large genome sequencing studies are swiftly being accepted as the new norm, it is pivotal for variant carriers, families, clinicians and genetic counsellors to be aware of what the potential risk is for variants of interest. Based on the current data shown here, there is inadequate evidence to categorise the PINK1 p.G411S or any other pathogenic PINK1 variants in heterozygous state as a major risk factor or causative for PD.
These results and findings may be especially relevant in genetic counselling of heterozygous PINK1 PD patients, who are obligate mutation carriers. And so, in summary, after data combination and analyses, this study indicates that there was no evidence found to corroborate a role for heterozygous PINK1 mutations as a robust risk factor for PD.
Original source: L Krohn, F. P. Grenn, M. B. Makarious, J. J. Kim, S Bandres-Ciga, D. A. Roosen, Z Gan-Or, M. A. Nalls, A. B. Singleton and C Blauwendraat. “Comprehensive assessment of PINK1 variants in Parkinson’s Disease”. Neurobiology of Aging Vol. 91. (July 2020)