We tested for systemic biases using the genomic inflation factor (lambda), LD-score regression, and QQ-plots (Supplementary Fig. using PD patients with probable RBD (PD+pRBD) and controls without PD or RBD ( N cases = 1782, N controls = 131,250), meta-analyzed for a total of 2843 cases and 139,636 controls. To identify genetic risk loci across the genome associated with RBD, we performed a case–control GWAS of iRBD ( N cases = 1061, N controls = 8386) and a case–control GWAS from 23andMe, Inc. Genome-wide association study identifies five RBD loci Using the GWAS summary statistics, we studied the genetic relationship between RBD and the synucleinopathies to which it progresses, as well as other conditions and exposures of interest. We further examined the biological implications of the nominated risk loci through pathway analysis, investigated variant effects on gene expression, and assessed the cumulative risk using polygenic risk score (PRS). To better understand RBD and early alpha-synucleinopathy genetics and potential mechanisms, we performed a genome-wide association study (GWAS) on 2843 cases and 139,636 controls. Thus far, the genetics of RBD has only been studied through the candidate gene approach. Overall, RBD, and specifically iRBD, appears to represent a more malignant subtype of alpha-synucleinopathies. Those with iRBD may have more frequent autonomic onset of MSA, less frequent parkinsonism at MSA onset, and a more severe disease course 7. MSA patients also have a high prevalence of RBD, estimated at 75–95%, 40% of which have iRBD. RBD is more frequent in DLB, found in ~50–80% of all cases, and is associated with increased severity of DLB symptoms and rapid deterioration 6. The presence of RBD is currently the strongest predictor for the development of dementia in PD 5 and is associated with more rapid progression of non-motor symptoms 3. In this manuscript, we will use “RBD” to refer to all instances of RBD regardless of at which stage symptoms present, and iRBD or sRBD to specify before or after overt neurodegeneration diagnosis, respectively. Approximately 30–60% of PD patients have RBD, including both iRBD and RBD as a symptom occurring after PD diagnosis (symptomatic RBD, sRBD) 3. There is strong evidence that iRBD also represents distinct, more severe subtypes of alpha-synucleinopathies. Since PD, DLB, and MSA are all characterized by accumulation of the protein alpha-synuclein, iRBD is considered a prodromal alpha-synucleinopathy, which offers a unique opportunity to identify these conditions at a much earlier stage 4. It is still unclear whether the remaining iRBD patients who did not convert at long follow-up will eventually convert, and pathological and imaging studies of this specific population are warranted. Over 80% of iRBD patients will convert within 10–15 years on average, to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), or in rare cases, multiple system atrophy (MSA) 2, 3. Isolated RBD (iRBD), defined as having RBD without other significant clinical neurological signs, is the only early highly predictive clinical marker for some neurodegenerative diseases. Rapid-eye-movement (REM) sleep behavior disorder (RBD), defined as loss of muscle atonia and dream enactment during REM sleep, is one of the most unique conditions in neurology 1. Nature Communications volume 13, Article number: 7496 ( 2022) Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |