rs10839553 — CCKBR

Intronic variant near the cholecystokinin B receptor gene associated with restless legs syndrome risk through dopaminergic signaling in the basal ganglia

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CCKBR and Restless Legs Syndrome — A Neuropeptide Gateway to Dopaminergic Signaling

Restless legs syndrome (RLS) is a neurological disorder affecting up to 10% of older adults, characterized by an irresistible urge to move the legs — typically worse at rest and at night. The core pathophysiology involves dopaminergic dysfunction in the basal ganglia11 dopaminergic dysfunction in the basal ganglia
the striatum and associated circuits that coordinate movement and sensory processing rely on tightly regulated dopamine signaling. The CCKBR gene encodes the cholecystokinin B receptor22 cholecystokinin B receptor
a G-protein coupled receptor expressed in neurons throughout the brain, where it responds to the neuropeptide cholecystokinin (CCK) and gastrin, a seven-transmembrane receptor that modulates dopamine release in the striatum and nucleus accumbens. Rs10839553 lies approximately 57 kb upstream of CCKBR on chromosome 11p15.4, within an intron of the non-coding transcript LOC101927825, where it likely acts as a regulatory variant influencing CCKBR expression.

The Mechanism

CCK-B receptors and dopamine D2 receptors have a well-documented antagonistic relationship in the nucleus accumbens33 nucleus accumbens
the ventral striatum hub that processes both reward and sensorimotor signals critical for RLS pathophysiology. When CCK acts through CCK-B receptors, it suppresses dopaminergic transmission — demonstrated directly by the finding that a selective CCK-B antagonist completely blocks CCK-induced dopamine release in the nucleus accumbens44 a selective CCK-B antagonist completely blocks CCK-induced dopamine release in the nucleus accumbens. Conversely, mice lacking the CCK-B receptor show significantly reduced dopamine D2 receptor expression in the nucleus accumbens55 mice lacking the CCK-B receptor show significantly reduced dopamine D2 receptor expression in the nucleus accumbens, confirming that tonic CCK-B signaling calibrates baseline dopaminergic tone.

Rs10839553 is an intronic variant in the chromosomal neighborhood of CCKBR. The rare C allele at this locus is associated with increased RLS risk, consistent with altered CCK-B receptor expression or function leading to reduced dopaminergic signaling in the basal ganglia — the same dopamine insufficiency that underpins RLS symptoms. The regulatory mechanism likely involves altered transcription factor binding or chromatin accessibility at this locus, influencing CCKBR transcript levels in relevant brain regions.

The Evidence

Rs10839553 reached genome-wide significance in the definitive 2024 RLS GWAS meta-analysis by Schormair et al.66 definitive 2024 RLS GWAS meta-analysis by Schormair et al., the largest RLS genetic study ever conducted, with 116,647 cases and 1,546,466 controls of European ancestry. The study identified 164 risk loci in total — an eightfold increase from prior work — with rs10839553 achieving p = 4×10⁻¹⁶, far exceeding the genome-wide significance threshold. The A allele (frequency ~91%) is protective; the C allele (~9%) confers increased risk. The study prioritized druggable genes including neuropeptide and glutamate receptors, positioning CCKBR as a potential therapeutic target.

Earlier GWAS work established the genetic architecture of RLS progressively: Winkelmann et al. 200777 Winkelmann et al. 2007 first identified MEIS1, BTBD9, and MAP2K5/LBXCOR1 — loci each conferring over 50% increased RLS risk. The 2017 Lancet Neurology meta-analysis88 2017 Lancet Neurology meta-analysis expanded this to 19 replicated loci in 45,896 cases, with MEIS1 remaining the strongest risk factor (OR 1.92). Rs10839553 was identified in the 2024 wave, reflecting the statistical power required to detect this association.

The CCKBR pathway connection to RLS is mechanistically coherent: dopamine deficiency in the striatum and spinal cord is the leading hypothesis for RLS pathogenesis, explaining why dopaminergic agonists (pramipexole, ropinirole, rotigotine) are the most effective first-line treatments. If CCKBR variants reduce basal dopaminergic tone in the basal ganglia, they could lower the threshold for RLS symptoms, particularly during the circadian trough in dopamine signaling that occurs at night.

Practical Implications

For C allele carriers, the actionable insight centers on supporting dopaminergic tone and addressing the iron deficiency that frequently exacerbates RLS. Brain iron is essential for dopamine synthesis — serum ferritin below 75 ng/mL correlates with RLS severity and responds to iron supplementation99 serum ferritin below 75 ng/mL correlates with RLS severity and responds to iron supplementation. Triggers that transiently reduce dopamine signaling (certain antihistamines, antiemetics, antipsychotics that block D2 receptors; selective serotonin reuptake inhibitors that can suppress dopamine release) may precipitate or worsen symptoms in genetically predisposed individuals. Caffeine effects are also dose-dependent for RLS — at high doses, caffeine can worsen symptoms by disrupting adenosine/dopamine balance.

Interactions

Rs10839553 acts within a broader RLS polygenic architecture. Key established loci include rs3785883 (MAPT — tau/neurodegeneration), rs6439886 (near MEIS1 — the strongest single RLS risk factor), and rs6777055 (near BTBD9 — iron homeostasis and periodic limb movements). Polygenic risk is additive; individuals carrying multiple RLS risk alleles across these loci have substantially higher cumulative risk than any single variant confers. The CCKBR/dopamine pathway and the BTBD9/iron pathway likely converge in the basal ganglia, where iron is required for tyrosine hydroxylase activity and dopamine synthesis.

Genotype Interpretations

What each possible genotype means for this variant.

AA Lower RLS Risk Normal

Two protective alleles; lower genetic risk for restless legs syndrome

You carry two copies of the common A allele at rs10839553, associated with lower genetic risk for restless legs syndrome from this locus. About 85% of people of European descent share this genotype. The A allele is thought to support normal CCK-B receptor expression and, in turn, adequate dopaminergic signaling in the basal ganglia. This does not eliminate your RLS risk entirely — RLS is polygenic and environmental factors matter — but this particular locus does not contribute elevated risk.

AC Intermediate RLS Risk Intermediate

One copy of the risk allele; moderately elevated genetic predisposition to restless legs syndrome

RLS has a strong genetic component, and rs10839553 is one of 164 genome-wide significant loci identified in the 2024 meta-analysis by Schormair et al. (PMID 38839884). The per-allele effect is modest in isolation, but CCKBR's role in calibrating dopaminergic tone in the basal ganglia provides a plausible mechanism. Heterozygous carriers have one copy of the risk allele alongside one protective A allele, likely resulting in intermediate CCKBR expression and slightly suboptimal dopaminergic support compared to AA homozygotes.

The most actionable modifiable risk factor for RLS is iron status — serum ferritin below 75 ng/mL substantially amplifies dopamine pathway dysfunction. Keeping iron stores replete is particularly important for those with genetic predisposition. Certain medications (especially dopamine antagonists such as metoclopramide, prochlorperazine, haloperidol, and some antidepressants) can precipitate or unmask subclinical RLS.

CC Higher RLS Risk High Risk

Two copies of the risk allele; substantially elevated genetic predisposition to restless legs syndrome

Restless legs syndrome is a condition where inadequate dopaminergic signaling in the basal ganglia and spinal cord produces uncomfortable sensory urges to move, typically worsening at night. The CCKBR gene encodes a receptor that, when activated by cholecystokinin, enhances dopamine release in the nucleus accumbens — a key node in the circuit affected in RLS.

The CC genotype at rs10839553 carries the highest risk conferred by this specific locus. In the Schormair et al. 2024 meta-analysis of over 1.6 million individuals, this locus reached p = 4×10⁻¹⁶, providing robust statistical evidence. The additive model fits this variant: CC individuals carry roughly twice the per-allele risk contribution compared to AC heterozygotes.

Importantly, RLS is highly treatable. First-line treatments (dopaminergic agonists such as pramipexole, ropinirole, rotigotine) are effective, and iron supplementation resolves symptoms in iron-deficient patients. Understanding your genetic predisposition enables proactive management rather than years of undiagnosed symptoms.