Association of the circadian rhythm gene ARNTL/BMAL1 with personal anxiety among people aged 25–64 (WHO international program “MONICA-psychosocial (MOPSY)”)

Objective: to study associations between personal anxiety (PA) and single nucleotide polymorphism rs2278749 of the ARNTL gene among individuals aged 25–64 years living in Novosibirsk.

Material and methods. Under the WHO program “MONICA-psychosocial (MOPSY)”, a random representative sample of the population aged 25–64 years in Novosibirsk was studied (725 men, mean age – 43.4±0.4 years, response – 71.3%; 710 women, mean age – 44.8±0.4 years, response – 72%). The general examination was carried out according to standard methods included in the protocol of the WHO program. To assess PA, a form of Spielberger self-assessment scales was proposed. Every second respondent underwent genotyping of the studied polymorphisms of the ARNTL gene.

Results. The C/C genotype of the ARNTL gene was found in the general population in 60.7% of individuals (in 61.2% of men and 60.5% of women); the C/T genotype was found in 34.1% of individuals (in 35.1% of men and 33.5% of women) and the T/T genotype in the general population was found in 5.2% of individuals (in 3.7% of men and 6% women). The probability of PA development among carriers of the CT+TT genotypes of the ARNTL gene was 2 times higher (p<0.05) in the general population and 2.4 times (p<0.05) among women; among T allele carriers, it was 1.8 times higher (p<0.05) in the population and 2.1 times (p<0.05) among women. Carriers of the C/T genotype of the ARNTL gene were 30.3% more likely to believe that they almost always take everything too personally (p=0.024). Carriers of the C/T genotype (21%) almost always, and carriers of the T/T genotype (27.8%) often would like to be as happy as others (p=0.031). The answer “I often feel satisfaction” prevailed (38.2%) among the carriers of the C/C genotype, and the answer “Almost never feel satisfaction” among the carriers of the C/T genotype (5.9%) of the ARNTL gene (p=0.044) .

Conclusion. It was found that the C/C genotype of the ARNTL gene was the most common in the population; the probability of PA occurrence among carriers of CT+TT genotypes, carriers of the T allele is 2 times higher than in carriers of other genotypes of the ARNTL gene.

1. Podkolodnaya OA, Podkolodnaya NN, Podkolodnyy NL. Mammalian circadian clock: gene network and computer analysis. Vavilovskiy zhurnal genetiki i selektsii. 2014;18(4/2):928-38 (In Russ.).

2. Vitaterna MH, King DP, Chang AM, et al. Mutagenesis and mapping of a mouse gene, clock, essential for circadian behavior. Science. 1994;264(5159):719-25. doi: 10.1126/science.8171325

3. Ikeda M, Nomura M. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem Biophys Res Commun. 1997;233(1):258-64. doi: 10.1128/MCB.16.4.1706

4. Zhou YD, Barnard M, Tian H, et al. Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system. Proc Natl Acad Sci U S A. 1997;94(2):713-8. doi: 10.1073/pnas.94.2.713

5. Ikeda M, Yu W, Hirai M, et al. cDNA cloning of a novel bHLH-PAS transcription factor superfamily gene, BMAL2: Its mRNA expression, subcellular distribution, and chromosomal localization. Biochem Biophys Res Commun. 2000;275(2):493-502. doi: 10.1006/bbrc.2000.3248

6. Sasaki M, Yoshitane H, Du NH, et al. Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription. J Biol Chem. 2009;284(37):25149-59. doi: 10.1074/jbc.M109.040758

7. Kovanen L, Saarikoski ST, Aromaa A, et al. ARNTL (BMAL1) and NPAS2 Gene Variants Contribute to Fertility and Seasonality. PLoS One. 2010;5(4):e10007. doi: 10.1371/journal.pone.0010007

8. Lavtar P, Rudolf G, Maver A, et al. Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis. PLoS One. 2018;13(1):e0190601. doi: 10.1371/journal.pone.0190601

9. Nievergelt CM, Kripke DF, Barrett TB, et al. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(3):234-41. doi: 10.1002/ajmg.b.30252

10. Robilliard DL, Archer SN, Arendt J, et al. The 3111 clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J Sleep Res. 2002;11(4):305-12. doi: 10.1046/j.1365-2869.2002.00320.x

11. Pedrazzoli M, Louzada FM, Pereira DS, et al. Clock polymorphisms and circadian rhythms phenotypes in a sample of the brazilian population. Chronobiol Int. 2007;24(1):1-8. doi: 10.1080/07420520601139789

12. World Health Organization. MONICA Psychosocial Optional Study. Suggested Measurement Instruments. Copenhagen: WHO Regional Office for Europe; 1988.

13. Spielberger CD. Anxiety as an emotional state. Anxiety: Current trends in theory and research. New York: Academic Press, 1972. Vol. 1. P. 24-49.

14. MONICA Monograph and Multimedia Sourcebook. Helsinki; 2003; 237 p.

15. Byuyul A, Tsefel P. SPSS: iskusstvo obrabotki informatsii. Analiz statisticheskikh dannykh i vosstanovlenie skrytykh zakonomernostey [SPSS: data processing art. Analysis of statistical data and restore hidden patterns]. Transl. from German. St. Petersburg: LLC “DiaSoftYuP”. 2002. 608 p. (In Russ.).

16. Pandis N. The chi-square test. Am J Orthod Dentofacial Orthop. 2016;150(5):898-9. doi: 10.1016/j.ajodo.2016.08.009

17. Sharashova EE, Kholmatova KK, Gorbatova MA, Grzhibovskiy AM. Multivariable logistic regression using SPSS software in health research. Nauka i zdravookhraneniye. 2017;(4):5-26 (In Russ.).

18. Papadimitriou GN, Linkowski P. Sleep disturbance in anxiety disorders. Int Rev Psychiatry. 2005;17(4):229-36. doi: 10.1080/09540260500104524

19. Takahashi JS, Hong H-K, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nat Rev Genet. 2008;9:764-75. doi: 10.1038/nrg2430

20. Rosbash M, Bradley S, Kadener S, et al. Transcriptional feedback and definition of the circadian pacemaker in Drosophila and animals. Cold Spring Harb Symp Quant Biol. 2007;72:75-83. doi: 10.1101/sqb.2007.72.062

21. Rijo-Ferreira F, Takahashi JS. Genomics of circadian rhythms in health and disease. Genome Med. 2019;11:82. doi: 10.1186/s13073019-0704-0

22. Corbett BA, Schupp CW, Levine S, Mendoza S. Comparing cortisol, stress, and sensory sensitivity in children with autism. Autism Res. 2009;2:39-49. doi: 10.1002/aur.64

23. Landgraf D, Long JE, Proulx CD, et al. Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxietylike Behavior in Mice. Biol Psychiatry. 2016;80(11):827-35. doi: 10.1016/j.biopsych.2016.03.1050

24. Hogenesch JB, Gu YZ, Jain S, Bradfield CA. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc Natl Acad Sci USA. 1998;95:5474-9. doi: 10.1073/pnas.95.10.5474

25. Bunger MK, Wilsbacher LD, Moran SM, et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103:1009-17. doi: 10.1016/s00928674(00)00205-1

26. Partonen T, Treutlein J, Alpman A, et al. Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med. 2007;39:229-38. doi: 10.1080/07853890701278795

27. Gafarov VV, Gagulin IV, Gromova EA, et al. Association of polymorphism rs2278749gene ARNTL with certain affective disorders and sleep disorders in the male population of Novosibirsk, aged 25–44. Mir nauki, kul’tury, obrazovaniya. 2016;6(61):315-9 (In Russ.).