Comprehensive assessment of PINK1 variants in Parkinson’s disease

Abstract

Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large datasets totalling 376,558 individuals including: 13,708 Parkinson's disease cases and 362,850 controls. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a risk factor for Parkinson's disease.

Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

“…7,8 However, the possible role of monoallelic pathogenic PINK1 and PRKN mutations in Parkinson's disease remains a matter of vivid debate: a recent study found 0.089% of monoallelic PINK1 mutation carriers in cases compared to 0.071% in controls in a large population screen (n=376,558). 9 Another study did not find any associations between PRKN variants and risk of Parkinson's disease. Pathogenic and likely-pathogenic heterozygous single nucleotide variants and copy-number variations were less frequent in Parkinson's disease patients (1.52%) compared to controls (1.8%).…”

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder

“…In order to examine the genetic basis of iRBD and its conversion, recent studies have examined whether PD-or DLB-associated genes are also associated with iRBD and whether they affect its conversion. It was demonstrated that while some genes such as GBA (Krohn et al, 2019b), TMEM175 (Krohn et al, 2019a) and SNCA (Krohn et al, 2019c) are associated with iRBD, other PD and DLB genes such as LRRK2 (Ouled Amar Bencheikh et al, 2018), APOE (Gan-Or et al, 2017) and MAPT (Li et al, 2018) are not. However, the association between SMPD1 and iRBD has not been investigated.…”

SMPD1 variants do not have a major role in REM sleep behavior disorder

“…In order to examine the genetic basis of iRBD and its conversion, recent studies have examined whether PD-or DLB-associated genes are also associated with iRBD and whether they affect its conversion. It was demonstrated that while some genes such as GBA (Krohn et al, 2019b), TMEM175 (Krohn et al, 2019a) and SNCA (Krohn et al, 2019c) are associated with iRBD, other PD and DLB genes such as LRRK2 (Ouled Amar Bencheikh et al, 2018), APOE (Gan-Or et al, 2017) and MAPT (Li et al, 2018) are not. However, the association between SMPD1 and iRBD has not been investigated.…”