rs56051278 — GPD2

Intronic variant in GPD2 (mitochondrial glycerol-3-phosphate dehydrogenase), second-strongest signal (P=1.5×10⁻²⁹) from the first-ever motion sickness GWAS; the G allele is in high LD with a missense variant

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GPD2 and the Glucose Link to Motion Sickness

One in three people experiences clinically significant motion sickness, yet the biological reasons have long been obscure. In 2015, Hromatka et al.11 Hromatka et al.
Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis. Human Molecular Genetics published the first genome-wide association study of motion sickness in 80,494 individuals from 23andMe — and found 35 genome-wide-significant loci spanning inner-ear development, neurological processes, and, unexpectedly, glucose homeostasis. The second strongest signal in the entire study was rs56051278, located in an intron of GPD2 on chromosome 2 (P = 1.5×10⁻²⁹, beta = +0.066 per G allele).

The Mechanism

GPD2 encodes mitochondrial glycerol-3-phosphate dehydrogenase22 mitochondrial glycerol-3-phosphate dehydrogenase
a FAD-dependent enzyme on the inner mitochondrial membrane that oxidises glycerol-3-phosphate to dihydroxyacetone phosphate, transferring electrons into the mitochondrial electron transport chain and regenerating cytosolic NAD⁺ from NADH produced during glycolysis — a process called the glycerol phosphate shuttle. This shuttle is critical for sustaining glycolysis in tissues that rely on rapid glucose oxidation, including neurons and intestinal smooth muscle cells.

rs56051278 is an intronic variant, but it is in high linkage disequilibrium (r² ≈ 0.8)33 high linkage disequilibrium (r² ≈ 0.8)
LD means these two variants are nearly always inherited together with rs2116665, a missense variant in GPD2 (R264H) previously associated with elevated free fatty acid and glycerol levels in plasma — biomarkers of glucose intolerance.

The downstream physiology connects to the GI tract in a specific way: during vestibular stimulation, glucose regulation is perturbed. A dedicated experimental study by Mo et al. 201244 Mo et al. 2012
Acute hyperglycemia is related to gastrointestinal symptoms in motion sickness. Physiological Behavior found that individuals who developed nausea and vomiting during motion exposure had significantly lower pre-exposure insulin than those who did not (P<0.05), and that acute hyperglycemia was greater in the symptomatic group. In a rat arm of the same study, pre-treating animals with insulin before acceleration significantly reduced the motion sickness index. The authors concluded that "stable glucose levels can help to relieve gastrointestinal symptoms in motion sickness." GPD2's role in sustaining neuronal and smooth-muscle glucose metabolism positions it as a plausible biological link between this genetic signal and the clinical phenotype.

The Evidence

The Hromatka GWAS enrolled 80,494 individuals of European ancestry drawn from the 23andMe cohort. Motion sickness susceptibility was self-reported. rs56051278 reached P = 1.5×10⁻²⁹ with a beta of +0.066 per G allele (effect allele). This is a well-powered association — the signal at the GPD2 locus was among the top two genome-wide.

The glucose-homeostasis cluster of hits (also including variants near UBE2E2, GPR26, RGS5, and NR2F2) was highlighted as a biologically coherent group distinct from the inner-ear development loci.

Interactions

rs56051278 is a tag SNP for the missense variant rs2116665 (R264H in GPD2) — the two are in high LD (r² ≈ 0.8) and should not be treated as independent associations. Future analysis comparing carriers of both to carriers of only one tag should be interpreted cautiously. The strongest hit in the same GWAS was rs66800491 near PVRL3.

Nutrient Interactions

carbohydrates altered_metabolism
glucose altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-susceptible Normal

No GPD2 motion sickness risk alleles — typical mitochondrial glucose handling during vestibular stress

You carry two copies of the A allele at rs56051278, meaning you do not carry the G allele linked to GPD2-mediated motion sickness susceptibility. This is the most common genotype globally (approximately 60% of people) and represents the reference state at this locus. In the large motion sickness GWAS of 80,494 individuals, A/A individuals were not enriched for motion sickness compared with the population average.

AG One Risk Allele Intermediate

One GPD2 motion sickness risk allele — modestly elevated susceptibility to motion-induced nausea

The G allele at rs56051278 is in high LD (r² ≈ 0.8) with rs2116665, a missense variant in GPD2 (R264H).

GG Two Risk Alleles High Risk

Two GPD2 motion sickness risk alleles — elevated susceptibility to motion-induced nausea and vomiting

rs56051278 tags the missense variant rs2116665 (R264H in GPD2) with which it is in high LD (r² ≈ 0.8).

Ginger's clinical evidence for motion sickness is substantial: multiple randomised controlled trials across car, sea, and postoperative nausea settings show consistent anti-emetic efficacy at 1–2 g doses.