Abstract
Mutations in the Parkin (PRKN) gene are the most frequent cause of autosomal recessive early-onset Parkinson's disease (PD). Heterozygous PRKN mutation carriers might also be at increased risk for developing clinical symptoms of PD. Given the high frequency of heterozygous mutations in the general population, it is essential to have better estimates of the penetrance of these variants, and to investigate, which clinical and biochemical markers are present in carriers and thus potentially useful for identifying those individuals at greater risk of developing clinical symptoms later in life. In the present study, we ascertained the frequency of heterozygous PRKN mutation carriers in a large population sample of the Cooperative Health Research in South Tyrol (CHRIS) study, and screened for reported PD risk markers. 164 confirmed heterozygous PRKN mutation carriers were compared with 2,582 controls. A higher number of heterozygous mutation carriers reported a detectable increase in an akinesia-related phenotype, and a higher percentage of carriers had manifested diabetes. We also observed lower resting heart rate in the PRKN mutation carriers. Extending our risk analyses to a larger number of potential carriers and non-carriers using genotype imputation (n = 299 carriers and n = 7,127 non-carriers), from previously published biomarkers we also observed a higher neutrophil-to-lymphocyte ratio (NLR) and lower serum albumin and sodium levels in the heterozygous PRKN variant carriers. These results identify a set of biomarkers that might be useful either individually or as an ensemble to identify variant carriers at greater risk of health issues due to carrier status.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in aging, second only to Alzheimer’s disease [1]
When extending our risk marker analyses to the imputed PRKN carrier dataset (n = 299 carriers and n = 7,127 non-carriers, Supplementary Table 2), we found higher neutrophil-to-lymphocyte ratio (NLR) (4.91 vs. 4.71, p = 0.025) and lower serum albumin (4.45 vs. 4.49, p = 0.008) and sodium levels (140.22 vs. 140.44, p = 0.047) in the PRKN variant carriers (Supplementary Table 3)
In the subset of the Cooperative Health Research in South Tyrol (CHRIS) study, for which exome sequence data are available (n = 3,603 participants), 164 individuals carried one of 17 known or newly detected heterozygous mutations in PRKN resulting in a carrier frequency of 4.55%
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in aging, second only to Alzheimer’s disease [1]. Mutations in PRKN (the gene that encodes Parkin) are the most common known cause of autosomal recessive early-onset PD, accounting for up to 42.2% of cases with an age of onset ≤20 years [4], and Parkin dysfunction represents a risk factor for sporadic PD [5]. The presence of heterozygous PRKN mutations is one of the reported potential genetic risk factors for PD [10, 14, 15]. Given the frequency (up to 3%) of heterozygous mutations in the population, it is essential to have better estimates of the penetrance of these variants and to investigate, which risk markers are manifesting in carriers and potentially useful for identifying those individuals at greater risk of clinical symptoms later in life. We screened for validated PD risk markers of the Movement Disorder Society (MDS) [18] and additional potential PD risk markers reported in the literature [19,20,21,22]
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