Neurotransmitter & Circadian Variants - References

Neurotransmitter & Circadian Variants — Literature Dossier

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Landmark Peer-Reviewed Studies

1. Egan et al. (2003) — The BDNF Val66Met Polymorphism and Activity-Dependent Secretion

• Citation: Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., … & Lu, B. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112(2), 257–269.
• Identifiers: DOI: 10.1016/s0092-8674(03)00035-7 (DOI · SciDB · Scholar) | PMID: 12553913 (PubMed · Europe PMC)
• Study Design & Cohort: Multi-modal human cohort ($N=641$ participants evaluated via Wechsler Memory Scale, fMRI, and proton magnetic resonance spectroscopy [NAA]) combined with hippocampal neuronal transfection assays.
• Quantitative Findings & Diagnostic Thresholds:
  • Met allele carriers (rs6265 A) exhibited significantly lower delayed episodic memory scores ($p=0.0002$), abnormal hippocampal fMRI activation ($p=0.004$), and lower hippocampal N-acetylaspartate (NAA, a marker of neuronal integrity, $p=0.017$).
  • Neuronal assays confirmed that while constitutive BDNF secretion was unchanged, depolarization-induced (activity-dependent) BDNF secretion was reduced by ~30% in Met-expressing neurons due to defective targeting to secretory granules.

2. Cornelis et al. (2006) — CYP1A2 Genotype, Coffee Intake, and Myocardial Infarction Risk

• Citation: Cornelis, M. C., El-Sohemy, A., Kabagambe, E. K., & Campos, H. (2006). Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA, 295(10), 1135–1141.
• Identifiers: DOI: 10.1001/jama.295.10.1135 (DOI · SciDB · Scholar) | PMID: 16522833 (PubMed · Europe PMC)
• Study Design & Cohort: Case-control study ($N=2,014$ cases with first acute nonfatal myocardial infarction and $2,014$ population-based matched controls) genotyped for CYP1A2 rs762551 (*1A fast vs. *1F slow).
• Quantitative Findings & Diagnostic Thresholds:
  • Among slow caffeine metabolizers (*1F C-allele carriers), consuming $2–3\text{ cups/day}$ of coffee conferred an adjusted MI Odds Ratio of $1.36$ ($95\%\text{ CI }1.01–1.83$) and $\ge 4\text{ cups/day}$ conferred an $\text{OR of }1.64$ ($95\%\text{ CI }1.14–2.34$); in adults aged $<50\text{ years}$, the OR reached $4.07$ ($95\%\text{ CI }1.89–8.74$).
  • Conversely, among fast metabolizers (*1A/*1A), $2–3\text{ cups/day}$ was cardioprotective ($\text{OR }0.78$, and $\text{OR }0.48$ in adults $<50$).

3. Rétey et al. (2007) — ADORA2A Polymorphism Modulates Caffeine Sensitivity and EEG Slow-Wave Sleep

• Citation: Rétey, J. V., Adam, M., Khatami, R., Luhmann, U. F., Jung, H. H., Berger, W., & Landolt, H. P. (2007). A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clinical Pharmacology & Therapeutics, 81(5), 692–698.
• Identifiers: DOI: 10.1038/sj.clpt.6100102 (DOI · SciDB · Scholar) | PMID: 17329997 (PubMed · Europe PMC)
• Study Design & Cohort: Questionnaire screening ($N=4,329$) followed by double-blind crossover polysomnography / high-density EEG sleep deprivation challenge with $2\times 200\text{ mg}$ caffeine vs. placebo in genotyped subjects ($N=22$).
• Quantitative Findings & Diagnostic Thresholds:
  • ADORA2A 1976C>T (rs5751876) genotype strongly predicted self-reported caffeine-induced insomnia ($p=0.007$) and electroencephalographic (EEG) beta ($16–20\text{ Hz}$) hyperarousal and suppression of slow-wave sleep delta activity ($p<0.03$).

4. Patke et al. (2017) — Mutation of the Human Circadian Clock Gene CRY1 in Delayed Sleep Phase Disorder

• Citation: Patke, A., Murphy, P. J., Onat, O. E., Krieger, A. C., Özçelik, T., Campbell, S. S., & Young, M. W. (2017). Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell, 169(2), 203–215.
• Identifiers: DOI: 10.1016/j.cell.2017.03.027 (DOI · SciDB · Scholar) | PMID: 28388406 (PubMed · Europe PMC) | PMCID: PMC5479574 (PMC Full Text)
• Study Design & Cohort: Whole-exome sequencing, 14-day inpatient circadian isolation laboratory monitoring, and reverse-genetics transcriptional assays across 6 kindreds ($N=70$ family members) and population biobanks.
• Quantitative Findings & Diagnostic Thresholds:
  • The CRY1 c.1657+3A>C (rs184039278, allele frequency $0.6\%$) causes skipping of exon 11, increasing the affinity of CRY1 for CLOCK and BMAL1, which lengthens the endogenous circadian period ($\tau$) by ~30–60 minutes and delays Dim-Light Melatonin Onset (DLMO) by $2–4\text{ hours}$ ($\text{OR }18.8,p=1.7\times 10^{-6}$).