Additional rare variant analysis in Parkinson’s disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance

Abstract

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson’s (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

“…Interestingly, in one report, PARK9 variants were implicated to co-occur with either GBA1 variants or alleles of another PD gene, leucine-rich repeat kinase (LRRK2). 96 Given the rarity of PARK9 mutations, definitive confirmation of a potential association with PD risk will require sequencing of much larger sample sizes.…”

Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson’s disease

“…Notably, enrichment of additional rare ATP13A2 variants was recently reported in LRRK2- associated PD [41]. Larger studies of patients with 22q11.2DS-associated PD will help clarify if additional rare variants in known PD genes could impact penetrance of PD in this genetic population.…”

Whole‐exome sequencing for variant discovery in blepharospasm

“…Recessive mutations in ATP13A2 have been linked to Kufor–Rakeb syndrome (Ramirez et al., ) and spastic paraplegia 78 (Estrada‐Cuzcano et al., ), both of which may include dystonia as a clinical manifestation. Variants in ATP13A2 may also contribute to oligogenic inheritance in PD (Lubbe et al., ). In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E‐04, Data ), and deleterious variants in UBR4 (OMIM 609890; rs748114415, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E‐04, Data ), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E‐04, Data ) were identified in the DYT13 (Chr1) locus.…”