rs73598374

mixedMag 3.5

This is a protein-altering variant in the ADA gene.

Key Literature Trait Associations

Slow-Wave Sleep Depth

Carriers of the ADA A allele (Asp8Asn, ~20-30% reduced enzyme activity) accumulate higher extracellular adenosine compared to G/G homozygotes. Because adenosine is the primary endogenous sleep-promoting molecule, elevated adenosine drives greater slow-wave activity (delta 0.75-1.5 Hz) in NREM stage 3/4 sleep. In controlled polysomnography studies (n=14 matched pairs), G/A individuals showed enhanced delta oscillation amplitude, fewer nocturnal awakenings, and more consolidated deep sleep than G/G controls. A large epidemiological replication in 800 subjects confirmed higher delta and theta spectral power across multiple sleep stages in A-allele carriers.

Bachmann V et al. “Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans.” Cerebral Cortex (new York, N.y. : 1991) (2012)

Allele A

OR —

p —

N 220

Candidate gene study

European

Rétey JV et al. “A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans.” Proceedings of the National Academy of Sciences of the United States of America 102(43):15676-15681 (2005)

Allele A

OR —

p 4.0e-2

Candidate gene study

Reichert CF et al. “The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements.” Plos One (2014)

Allele A

OR —

p —

N 24

Candidate gene study

European

Sleep EEG Spectral Power

In the EPISONO epidemiological cohort (800 participants, full-night PSG), ADA A-allele carriers showed significantly higher EEG spectral power in delta frequencies during NREM stages 1 and 3+4, and elevated theta power during stages 1, 2, and REM sleep. The findings establish ADA rs73598374 as an important source of inter-individual variation in sleep homeostasis, mediated by reduced adenosine catabolism and consequent enhancement of A1/A2A receptor-mediated sleep-promoting signaling.

Bachmann V et al. “Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans.” Cerebral Cortex (new York, N.y. : 1991) (2012)

Allele A

OR —

p —

N 220

Candidate gene study

European

Mazzotti DR et al. “Adenosine deaminase polymorphism affects sleep EEG spectral power in a large epidemiological sample.” Plos One 7(8):e44154 (2012)

Allele A

OR —

p 5.0e-2

Candidate gene study

Reichert CF et al. “The circadian regulation of sleep: impact of a functional ADA-polymorphism and its association to working memory improvements.” Plos One (2014)

Allele A

OR —

p —

N 24

Candidate gene study

European

Reichert CF et al. “Insights into behavioral vulnerability to differential sleep pressure and circadian phase from a functional ADA polymorphism.” Journal of Biological Rhythms (2014)

Allele A

OR —

p —

N 24

Candidate gene study

European

Leukocyte telomere length

A single candidate-gene study (Concetti et al., 2015) found that A-allele carriers of rs73598374 had lower telomerase activity (p=0.019) and shorter leukocyte telomere length (p=0.003) compared to G/G homozygotes. A-allele carriers also showed a steeper age-related decline in telomere length (r=−0.314, p=0.005 vs r=−0.243 for G/G). The proposed mechanism is that elevated adenosine from reduced ADA activity accelerates replicative senescence. Evidence is preliminary — the study was small, no replication has been published, and the clinical significance of the observed telomere difference is unclear.

Concetti F et al. “The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length.” European Journal of Human Genetics : Ejhg (2015)

Allele A

OR —

p 3.0e-3

Candidate gene study

European

Sleep quality

Tartar et al. (2021) reported that A-allele carriers had significantly higher evening melatonin levels and better self-reported sleep quality compared to G/G homozygotes. The authors propose that elevated adenosine from reduced ADA activity potentiates melatonin secretion, reinforcing circadian sleep pressure. However, the study did not report its sample size in the abstract, and the finding has not been independently replicated. The relationship between ADA genotype and mood-sleep associations was also altered, with stronger mood–sleep correlations in G/G individuals. This association is considered preliminary.

Tartar JL et al. “A Functional Adenosine Deaminase Polymorphism Associates with Evening Melatonin Levels and Sleep Quality.” Journal of Circadian Rhythms (2021)

Allele A

OR —

p —

Candidate gene study

multi-ancestry

Platelet reactivity

Verdoia et al. (2020) examined rs73598374 in 464 acute coronary syndrome patients treated with ticagrelor (a drug whose mechanism involves adenosine signaling). No significant differences in platelet reactivity or high residual platelet reactivity were observed between A-allele carriers and G/G homozygotes (adjusted OR 1.17, 95% CI 0.64–2.14, p=0.61). A-allele carriers showed a numerically lower — but non-significant — rate of recurrent ACS at follow-up. The study did not demonstrate a clinically meaningful pharmacogenomic interaction between this ADA variant and ticagrelor response.

Verdoia M et al. “Impact of the rs73598374 polymorphism of the adenosine deaminase gene on platelet reactivity and long-term outcomes among patients with acute coronary syndrome treated with ticagrelor.” Thrombosis Research (2020)

Allele A

OR 1.17

p 6.1e-1

N 464

Candidate gene study

European

▶

ClinVar annotation

Benign★★★★

12 submitters4 publications

Adenosine deaminase 2 allozyme; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency; not specified; not provided

View on ClinVar →

▶

Research that mentions this SNP (1)

▶

Disease variants in genomes of 44 centenarians

Case reportN=44Yun Freudenberg‐Hua et al.(2014)· Molecular Genetics & Genomic Medicine

Whole genome sequencing of 44 Ashkenazi Jewish centenarians identified 216 coding variants annotated as pathogenic or likely pathogenic in ClinVar. The study found 130 rare variants (MAF <5%) reported to cause degenerative, neoplastic, and cardiac diseases with various inheritance patterns. Notably, several carriers had no clinical manifestations despite carrying variants linked to serious diseases (e.g., an APOE ε4 homozygote without Alzheimer's disease, a UBQLN2 P525S carrier without ALS). These findings suggest incomplete penetrance and reduced clinical significance for many reported disease mutations.

Traits studied:Aging and longevityAlzheimer's diseaseAmyotrophic lateral sclerosisBecker muscular dystrophyBrugada syndromeCancer/NeoplasmCardiac arrhythmiaCardiomyopathyDeafnessDementia with Lewy bodiesDiabetesDuchenne muscular dystrophyEhlers-Danlos syndromeGaucher diseaseGlaucomaHypercholesterolemiaIchthyosisKeratoconusLong QT syndromeObesityParkinson's diseasePremature ovarian failureRetinitis pigmentosa

rs73598374

Key Literature Trait Associations

Slow-Wave Sleep Depth

Sleep EEG Spectral Power

Leukocyte telomere length

Sleep quality

Platelet reactivity

ClinVar annotation

Research that mentions this SNP (1)

Community Wiki

Comments