ADA D8N - GET-Evidence



(ADA Asp8Asn)

Short summary

This common variant is reported to reduce adenosine deaminase enzyme activity. It has been associated with an increased tendency for non-REM sleep — more slow wave sleep, less nocturnal wakings, and a stronger negative impact of sleep deprivation. A role for this gene and variant was previously proposed for autism susceptibility, but this is controversial and was not replicated by later studies.

Variant evidence

Enzyme involved in metabolism of adenosine, which is thought to be involved in sleep homeostasis. However, Polyphen 2 predicts “benign” effect.

Functional 1

Lower enzyme activity

See 7316475.

Case/Control 5

Significant effect on slow wave sleep reported by two different groups.

See Rétey JV et al. 2005 (16221767), Mazzotti DR et al. 2011 (21359089), Bachmann V et al. 2012 (21734253).

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr20:43280227: 3.0% (238/8058) in EVS
  • T @ chr20:42713640: 3.2% (2/62) in GET-Evidence
  • Frequency shown in summary reports: 3.0% (238/8058)


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PubMed PMID: 7316475


Hirschhorn R, Yang DR, Israni A. An Asp8Asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover. Ann Hum Genet. 1994 Jan;58(Pt 1):1-9. PubMed PMID: 8031011.

The authors characterize the amino acid change responsible for this common ADA variant, “ADA2”.

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PubMed PMID: 11354825

Following up on a study that reported that ADA activity was reduced in the sera of autistic children, this study measured the incidence of this variant in autistic subjects. Of 118 autistic subjects, 3 were homozygous and 37 were heterozygous for this variant. Of 126 controls, none were homozygous and 14 were heterozygous. When counting alleles, this results in case+: 43, case-: 193, control+: 14, control-: 238, resulting in an odds ratio of 3.7 with significance = 1.6 * 10^-5.

Rétey JV, Adam M, Honegger E, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15676-81. Epub 2005 Oct 12. PubMed PMID: 16221767; PubMed Central PMCID: PMC1266101.

This study found that heterozygous carriers of this variant are much more likely to report less nocturnal awakenings from sleep, sleep more deeply, and spend more time in slow wave sleep.

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PubMed PMID: 17340203

This study attempted to replicate findings in Italian studies, and concluded that ADA-D8N does not play any significant role in autism cases in the North American population. This may be due to population differences between the Italian families and the North American cases (the latter being more heterogeneous).

The authors note that the role of ADA activity in autism is controversial — the Italian studies were prompted by an observation of lower ADA enzyme activity in autism cases, but a later study contradicted that finding and found normal ADA activity levels.

Mazzotti DR, Guindalini C, Pellegrino R, Barrueco KF, Santos-Silva R, Bittencourt LR, Tufik S. Effects of the adenosine deaminase polymorphism and caffeine intake on sleep parameters in a large population sample. Sleep. 2011 Mar 1;34(3):399-402. PubMed PMID: 21359089; PubMed Central PMCID: PMC3041717.

This study finds less dramatic associations than Retey et al. Comparing carriers to non-carriers, a difference was only seen among the group of carriers that had consumed caffeine — when compared to caffeine-consuming non-carriers, carriers had lower sleep latency, higher sleep efficiency percentage, more REM sleep and fewer minutes awake. This may indicate carriers are less susceptible to sleep disruptive effects of caffeine.

However, there was no significant differences found between carriers and non-carriers in various self-reported traits (caffeine intake, restless legs syndrome, insomnia, sleep-promoting drugs). Also, the authors monitored arousals per hour for the subjects and found no significant difference between carriers and non-carriers (which contrasts with the self-reported data from Retey et al.). Findings may be less dramatic in this study because the subjects represent a highly heterogeneous epidemiological group.

Bachmann V, Klaus F, Bodenmann S, Schäfer N, Brugger P, Huber S, Berger W, Landolt HP. Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans. Cereb Cortex. 2012 Apr;22(4):962-70. Epub 2011 Jul 6. PubMed PMID: 21734253.

The authors are the same group as Retey et al. and report confirming their previous findings, interpreting the variant as causing higher non-REM sleep pressure.

They report carriers spend more time in slow wave sleep, high slow wave sleep EEG activity, higher sleepiness during sleep deprivation, higher saliva alpha-amylase activity with a strong diurnal cycle (a proposed biomarker of sleep pressure), and reduced sustained attention in response to sleep deprivation. They also found no difference in self-reported hours typically slept.


hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het T @ chr20:43280227


huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het T @ chr20:43280227


GS18555 - var-GS18555-1100-36-ASM
het T @ chr20:42713641


Other external references

  • rs73598374
  • Score: 0 (benign)
    Web search results (8469 hits -- see all)
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  • ada_oh.dat
    ... param name="channelName" type="string">Ada Public Library - OH</ptv:param> <ptv: ... "channelhomepage" type="string"></ptv:param> <ptv:param ...
  • qtrmoon.fts
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  • ada_id.dat
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Other in silico analyses

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 5

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Gene search

"GENE" or "GENE A123C":

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