The Genetic Basis of Probable REM Sleep Behavior Disorder in Parkinson’s Disease

Abstract

Patients with Parkinson’s Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD we compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data, dementia, psychiatric conditions, or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score > 5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45–7.93), SNCA_A53T_rs104893877 (8.21, 2.26–36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08–4.10), and ZNF184_rs9468199 (1.89, 1.08–3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15–0.78). The ML algorithms led to similar results. The predictive models were highly specific (95–99%) but lacked sensitivity (9–39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop pRBD in PD. Additional investigations are needed.

The Genetic Landscape of Sleep Disorders in Parkinson’s Disease

“…Moreover, in a recent study Perez-Lloret et al found that GBA _N370S_rs76763715 was associated with more frequent pRBD among PD patients. In addition, some GBA variants, like rs2230288/E326K, rs75548401/T369M, and rs369068553/V460L, were also associated with more frequent non-motor symptoms, including RBD, as well as with a more aggressive motor disease [ 13 ].…”

“…The zinc finger protein 184 ( ZNF184 ) is located on chromosome 6 and encodes a Kruppel C2H2-type zinc-finger protein family member, which participates in gene expression regulation [ 57 ]. The genetic basis of pRBD in PD was recently examined and the ZNF184 _rs9468199 polymorphism was found to increase the risk of pRBD [ 13 ]. This variant was previously associated with more frequent RBD in the Chinese population [ 58 ].…”

“…Interestingly, Camk2b knockout mice show reduced sleep, whereas the phosphorylation states of CaMK2 appear to control sleep induction and maintenance processes differently [ 60 ]. The ANK2.CAMK2D _rs78738012 polymorphism was recently found to increase the risk of pRBD [ 13 ].…”

“…The suprachiasmatic nucleus has been found to express high levels of SYT17 [ 62 ]. Interestingly, in the study of Perez-Lloret, the COQ7.SYT17 _rs11343 polymorphism was found to reduce pRBD risk [ 13 ]. Further studies are required to confirm these findings.…”

“…GBA mutations carriers-OR = 3.13 for pRBD sGBA and GD-PD had higher frequencies of RBD A recent meta-analysis PD heterozygous GBA patients-high risk RBD GBA variants, like N370S and L444P-higher RBD risk in PD patients GBA_N370S_rs76763715-more frequent pRBD among PD patients GBA variants, like rs2230288/E326K, rs75548401/T369M, and rs369068553/V460L-RBD [3,7,[11][12][13]…”