Objective: We hypothesized that heterozygosity for rare coding variants in PRKN, PINK1 or PARK7 might also represent a risk factor for sporadic late-onset PD.[4]

Background: Some mutations causing autosomal dominant Parkinson’s disease (PD) show reduced penetrance LRRK2 (e.g. G2019S), alpha-Synuclein (SNCA-duplication)) [1, 2]. Biallelic coding variants and gene dosage changes in the Parkin (PRKN), PTEN induced kinase 1 (PINK1) and Parkinson Associated Deglycase (PARK7) genes cause early onset PD.[3]

Method:
We performed pooled DNA sequencing of the PRKN, PINK1 and PARK7 genes in 4096 PD and 4096 controls of German ancestry. PD patients had a mean age at examination of 67 years, a mean age of onset of 60 years and 60% were male. Healthy controls had a mean age of 61 years and 56% were male.
We pooled equal amounts of DNA of 32 samples and processed these pools using a custom HaloPlex^© Target Enrichment System panel (Agilent, USA). VCF files were generated using the variant caller CRISP developed to detect rare single nucleotide variants (SNV) in pooled sequencing samples [5]. We restricted the analysis to missense, splice-site and stop-gain SNVs with a minor allele frequency (maf) below 1% and in the subgroup of SNVs predicted to be among the genomewide 1% most deleterious variants in the genome by a Combined Annotation Dependent Depletion phred-scaled (CADD-phred) score greater 20 [6]. We used the optimized sequence-kernel-association (SKAT-O) test to genewise assess the association with PD and adjusted the p-values for the 3 tested genes [7].

Results: We identified statistically significant associations between variants in PRKN and PD for both groups and for PARK7 in the subgroup with a CADD-phred score greater 20. A limitation of this study is the unknown type II error caused by the exclusion of true variants due to methodology (exclusion of CNVs, Indels, not detected gene dosage changes) or quality filtering (stringent quality thresholds). However, it is highly likely that the majority of rare variants in PRKN, PINK1 and PARK7 are associated with PD risk and that these variants are not protective. The here reported findings can motivate larger replication studies including more types of genetic variations in the future.

Conclusion: In summary, we present preliminary evidence that heterozygous variants in PRKN in moderate and private frequency are associated with late onset sporadic PD.

References: [1] Ahn TB, Kim SY, Kim JY, Park SS, Lee DS, Min HJ, et al. alpha-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology. 2008;70:43-9. [2] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583-90. [3] Puschmann A. Monogenic Parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations. Parkinsonism Relat Disord. 2013;19:407-15. [4] Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6:652-62. [5] Bansal V. A statistical method for the detection of variants from next-generation resequencing of DNA pools. Bioinformatics. 2010;26:i318-24. [6] Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886-D94. [7] Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012;91:224-37.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/moderately-frequent-and-private-variants-in-prkn-are-associated-with-late-onset-parkinsons-disease/