rs10005233 (SNCA): Parkinson's REM Sleep Disorder Risk
Key takeaways
- rs10005233-T is linked to roughly 21% higher odds of REM sleep behavior disorder in people already diagnosed with Parkinson's disease
- The variant lies in the SNCA gene region, which encodes alpha-synuclein, the protein that clumps abnormally in Parkinson's disease
- This genome-wide significant association was found across 18,423 Parkinson's patients in 15 research cohorts
- GTEx data links this variant to reduced expression of SNCA-AS1, a regulatory RNA near the SNCA gene, across multiple brain regions
- The findings distinguish Parkinson's subtypes rather than affecting who develops Parkinson's disease overall
Key takeaways
- rs10005233-T is linked to roughly 21% higher odds of REM sleep behavior disorder in people already diagnosed with Parkinson's disease
- The variant lies in the SNCA gene region, which encodes alpha-synuclein, the protein that clumps abnormally in Parkinson's disease
- This genome-wide significant association was found across 18,423 Parkinson's patients in 15 research cohorts
- GTEx data links this variant to reduced expression of SNCA-AS1, a regulatory RNA near the SNCA gene, across multiple brain regions
- The findings distinguish Parkinson's subtypes rather than affecting who develops Parkinson's disease overall
What the research says A genome-wide association study (GWAS — a large-scale scan comparing genetic variants across many individuals) compared 5,403 Parkinson's disease (PD) patients with probable REM sleep behavior disorder (RBD) to 13,020 PD patients without RBD across 15 international cohorts, identifying rs10005233-T as the strongest signal in the SNCA (alpha-synuclein) locus, with an odds ratio (OR) of 1.21 (95% confidence interval [CI] 1.16–1.27, p = 1.81 × 10⁻¹⁵). Two other independently acting variants in this locus — rs5019538-G (OR 0.85, p = 2.46 × 10⁻¹⁰) and rs356182-G (OR 0.89, p = 0.0001) — showed opposite effects on the same phenotype, indicating that this region harbors multiple independent signals with distinct directions of effect. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD+RBD was detected but did not survive correction for multiple comparisons.
Reported associations
- Parkinson's disease with probable REM sleep behavior disorder (PD+RBD): rs10005233-T is associated with higher odds of RBD in PD versus PD without RBD; OR = 1.21 (95% CI 1.16–1.27), p = 1.81 × 10⁻¹⁵, across 18,423 PD patients in 15 cohorts. The study used a case-only design limited to people already diagnosed with PD, not a general-population comparison.
Evidence quality The primary evidence comes from a multi-cohort GWAS of 18,423 PD patients (5,403 PD+RBD; 13,020 PD-RBD) across 15 research centers, with 23andMe contributing approximately 11,310 participants (roughly 61% of the total). The p-value of 1.81 × 10⁻¹⁵ substantially exceeds the conventional genome-wide significance threshold of 5 × 10⁻⁸. A key limitation is that RBD was assessed by questionnaire or self-report rather than polysomnography (the gold-standard sleep laboratory test), which may introduce misclassification of RBD status. The case-only design means findings cannot be extrapolated to general-population risk for PD or RBD. No conflicting signals for rs10005233 were identified within the reviewed literature, though only a single primary study was available.
Tissue-specific expression effects
- SNCA-AS1 (an antisense regulatory RNA transcribed from the DNA strand opposite to SNCA): the variant is associated with reduced expression in cerebellum, cerebellar hemisphere, anterior cingulate cortex, cortex, pituitary gland, and tibial nerve — spanning multiple brain regions and peripheral nervous tissue. GTEx Portal
- SNCA: the variant is associated with increased expression in the heart's left ventricle. This is a mechanistic tissue-level observation; whether this cardiac expression difference has clinical significance is not established. GTEx Portal
- MMRN1 (multimerin-1): the variant is associated with reduced expression in EBV-transformed lymphocyte cell lines. GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs10005233?
rs10005233 is a genetic variant located in the SNCA gene region, which encodes alpha-synuclein. Carrying the T allele has been associated with higher odds of REM sleep behavior disorder occurring in people already diagnosed with Parkinson's disease.
What does the SNCA gene do?
SNCA encodes alpha-synuclein, a protein that accumulates abnormally in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. These conditions are collectively called synucleinopathies because of this shared feature.
What is REM sleep behavior disorder and why does it matter in Parkinson's?
REM sleep behavior disorder (RBD) is a sleep condition where normal muscle paralysis during dreaming is absent, causing people to physically act out their dreams. In Parkinson's disease, its presence is associated with a more severe disease course, including faster progression and greater frequency of cognitive and neuropsychiatric symptoms.
Is rs10005233 linked to the risk of developing Parkinson's disease?
The available evidence used a case-only design comparing Parkinson's patients with and without RBD, not people with and without Parkinson's disease. The variant appears to mark a Parkinson's subtype rather than affecting general susceptibility to developing Parkinson's disease in the broader population.
What tissues does rs10005233 affect gene expression in?
According to GTEx data, this variant is associated with reduced expression of SNCA-AS1 in several brain regions and the pituitary, increased SNCA expression in the heart's left ventricle, and reduced MMRN1 expression in laboratory lymphocyte cell lines. These are mechanistic observations and their clinical significance is not established.