rs11584630 (KCNN3): Parkinson's disease variant
Key takeaways
- Machine learning identified rs11584630 in KCNN3 as potentially linked to Parkinson's disease, but standard genome-wide analysis did not
- Evidence is preliminary: one computational study of 8,840 participants, no independent replication reported
- The variant sits in a non-coding (intronic) region of KCNN3 and was surfaced by machine learning, not standard statistical thresholds
- In cerebellar brain tissue, the alternate allele is associated with increased expression of the CLK2 gene, based on GTEx v11 data
Key takeaways
- Machine learning analysis identified rs11584630, an intronic variant in KCNN3, as potentially relevant to Parkinson's disease (PD) risk in a study of 8,840 participants, even though standard genome-wide scanning did not flag it as significant
- The evidence is preliminary: a single computational study with no independent replication reported in the available literature
- The variant sits within a non-coding (intronic) region of this gene and was surfaced by machine learning feature importance scoring, not by standard statistical thresholds
- The alternate allele is associated with modestly increased CLK2 gene expression in cerebellar brain tissue, according to GTEx v11 data
What the research says rs11584630 is an intronic variant (a change within a non-coding segment of a gene) in KCNN3. A 2024 study (Rahman and Liu, Frontiers in Genetics) applied GWAS (genome-wide association study, a scan of hundreds of thousands of genetic variants to find disease associations) combined with machine learning to data from the Fox Insight online study, covering 8,840 participants and 447,089 single-nucleotide polymorphisms (SNPs, individual positions in the genome where people commonly differ by one DNA letter). The standard GWAS component did not flag rs11584630 as genome-wide significant, but feature importance analysis from the resulting machine learning models (a method that scores how much each variant contributed to the model's predictions) identified it as a potentially causative PD variant. The genomic prediction models achieved an AUC (area under the receiver operating characteristics curve; 1.0 is perfect, 0.5 is chance) of 0.74.
Reported associations
- Parkinson's disease: Flagged as a potentially causative intronic variant in KCNN3 through machine learning feature importance analysis of 8,840 Fox Insight participants; the variant did not reach genome-wide significance in the paired GWAS component of the same study
- CLK2 expression in Brain_Cerebellum: The alternate allele is associated with increased CLK2 gene expression in cerebellar brain tissue GTEx Portal
Evidence quality The association between rs11584630 and PD rests on a single study (Rahman and Liu, 2024) using 8,840 Fox Insight participants. The variant did not reach genome-wide significance (the standard threshold of p < 5 x 10^-8) in the study's own GWAS; it appeared only through machine learning feature importance scoring, which can surface sub-threshold signals but is also more susceptible to overfitting than standard GWAS. No independent replication of this finding has been reported in the provided studies. The GTEx v11 eQTL signal (eQTL: a genetic variant associated with changes in how much a nearby gene is expressed) for CLK2 in Brain_Cerebellum is statistically supported at FDR < 0.05 (p = 9.4e-6) but modest in effect size (slope +0.12 on a log2-normalized scale), and represents a correlational association rather than established functional causality. Overall, the evidence for this variant's role in PD is weak and preliminary.
Tissue-specific expression effects
- CLK2: The alternate allele is associated with increased expression in Brain_Cerebellum tissue, with a modest effect size (GTEx v11, FDR < 0.05, p = 9.4e-6) GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
Is rs11584630 linked to Parkinson's disease?
A 2024 study flagged rs11584630 as potentially relevant to Parkinson's disease through machine learning feature importance analysis of 8,840 participants. It did not reach standard genome-wide significance in the same study, so the finding is preliminary and requires independent replication.
What gene is rs11584630 found in?
rs11584630 sits within an intron (a non-coding segment) of the KCNN3 gene. Because it is intronic, it does not directly change a protein sequence, though intronic variants can influence nearby gene expression.
Why did standard genome-wide scans miss rs11584630?
Standard genome-wide association studies apply strict statistical thresholds to limit false positives. rs11584630 did not cross that threshold on its own. Machine learning feature importance methods can surface variants with smaller individual signals, which is how this variant was identified.
Does rs11584630 affect brain gene expression?
According to GTEx v11 data, the alternate allele of rs11584630 is associated with modestly increased expression of the CLK2 gene in cerebellar brain tissue. This is a correlational association and does not establish a direct functional mechanism.
How reliable is the evidence linking rs11584630 to Parkinson's disease?
The evidence is weak and preliminary. It comes from one computational study of 8,840 participants where the variant was flagged by machine learning rather than standard statistical analysis, and no independent replication has been reported in the available literature.