Genome-wide association study of REM-sleep behaviour disorder identifies new risk loci
Bibliographic record
Abstract
Abstract Rapid-eye-movement (REM)-sleep behaviour disorder (RBD) can be a prodromal stage of α-synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and provides a unique opportunity to study and understand early neurodegeneration. Previous research on RBD has identified common risk loci in several PD and DLB genes, but the full extent of its genetic architecture and disease-specific associations remain unknown. In the present study, we aimed to identify novel loci associated with RBD by conducting an updated European RBD genome-wide association study (GWAS). We performed a meta-analysis using a previous RBD GWAS and newly genotyped RBD patients and controls, resulting in a total of 3,564 RBD cases and 140,393 controls analyzed. We further assessed the functional impact of new associations using fine-mapping and colocalization analyses with adult brain expression quantitative trait loci (eQTLs). To confirm if novel RBD loci are implicated in additional synucleinopathy phenotypes, we examined common variant associations in GWASs of PD risk, DLB risk, PD with RBD risk, PD age at onset, and various measures of progression. Additionally, rare variants were analyzed with the optimal sequence kernel association test (SKAT-O) in PD and DLB whole genome sequencing cohorts. Lastly, we analyzed known PD- and DLB-risk loci for associations with RBD. We identified RCOR1 as a novel risk locus for RBD, with fine-mapping suggesting the association to be driven by a variant in intron 2. Colocalization revealed no evidence for shared genetic signals with brain eQTLs, although this may reflect a lack of statistical power to detect an association. Common and rare variants in the RCOR1 locus were not associated with PD, DLB, and additional α-synucleinopathy phenotypes. We observed several PD and DLB risk loci to be associated with RBD, including MAPT , STK39 , and SIPA1L2 . The MAPT associated variant tags the protective H2 haplotype, consistent with previous findings in PD. Several SNCA variants previously associated with PD or DLB were also associated with RBD, but with differing directions of effect, highlighting the complex genetic landscape underlying α-synucleinopathy subtypes. This study identifies new RBD loci and strengthens our understanding of the genetic modifiers underlying RBD. Further replication and functional studies will be required to validate our findings and explore their biological implications.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".