**3.3 Association of the polymorphism of the rs934945 PER2 gene with sleep disorders**

The prevalence of polymorphic variants of candidate gene of rs934945 *PER2* gene was as follows—homozygous genotype A/A—4.47%, heterozygous genotype A/G— 30.17%, and homozygous genotype G/G—65.36%. **Table 4** shows the frequency distribution of the rs934945 *PER2* gene among 25–44-year-old men in Novosibirsk.

Among individuals with the homozygous A/A genotype of the *PER2* gene, there was a growing tendency for anxiety dreams during sleep a total of 4–7 days per month (12.5%), compared with A/G genotype carriers (7.4%) and G/G genotype carriers (12%) (χ<sup>2</sup> = 13.83 df = 8 p = 0.08).

The carriers of the G/G genotype of the *PER2* gene were significantly less likely to wake up at night (51.9%) compared to men carrying the A/G (38.5%) and A/A (37.5%) genotypes. In contrast, men carrying the AA genotype were more likely (25%) to wake up (two or more times per night), a total of four to seven times per week, compared to the carriers of the A/G genotype (20.4%) and the G/G genotype (13.2%) (χ<sup>2</sup> = 25.76 df = 8 p = 0.004).


### **Table 4.**

*Polymorphism of rs934945* PER2 *gene in an open population of men aged 25–44 years (screening V).*

In the population of men aged 25–44 years, individuals carrying the A/A genotype of the *PER2* gene tended to have a shorter sleep duration of 5 hours or less (62.5%) compared to carriers genotypes A/G (57.4%) and G/G (41.9%) (χ<sup>2</sup> = 9.21 df = 10 p = 0.51).

### **3.4 Association of the polymorphism of the rs934945 PER2 gene with sleep disorders**

The prevalence of polymorphic variants of the candidate gene NPAS2 rs4851377 in the population was as follows—homozygous C/C genotype in 13.4%, heterozygous C/T genotype in 53.6%, and homozygous genotype T/T in 32.9%. The C allele of the NPAS2 candidate gene was found in 40.3% of men, and the T allele was found in 59.7% of men (**Table 5**).

In the population, the C/C genotype of the NPAS2 rs4851377 gene was significantly more common in those who slept at least 8 hours per night (33.3%) and 9 hours per night (33.3%), and the C/T and T/T genotypes were in those with 7 hours of sleep (50% and 53.3%, respectively) (χ<sup>2</sup> = 18.425 df = 10 p < 0.05).

It was found that 6-hour sleep 4.5 times (95% CI 0.735–27.536) was significantly more often observed among the carriers of the T allele than the C allele who had 9 hour sleep (χ<sup>2</sup> = 6.142 df = 1 p < 0.05); also 7-hour sleep versus 9-hour sleep was four times more often (95% CI 0.66–24.245) in carriers of the T allele than in carriers of the C allele (χ<sup>2</sup> = 5.488 df = 1 p < 0.05).

### **3.5 Association of VNTR polymorphisms of the DRD4 gene and VNTR polymorphism of the DAT gene with sleep disorders (screening III)**

In an open population of men aged 25–64 years, the frequency of homozygous genotype 4/4 of the dopamine receptor subtype 4 (*DRD4*) gene was 57.9%; genotype 2/2 was less frequent—6.1%, genotype 2/4—12.5%, and genotype 3/4—5.6%; even less frequent were—genotype 4/6—4.2%, genotype 2/6, genotypes 4/7 and 6/6 were present in equal proportions—2.1%. The frequency distribution of alleles showed that allele 4 prevails—found in 70.7%, allele 2 was found in 14%, allele 6—in 6%. The remaining alleles account for 0.8%–5.4% (**Table 6**).

### *Circadian Rhythm - New Insights into Physiological and Pathological Implications*


### **Table 5.**

*Polymorphism of rs4851377* NPAS2 *gene in an open population of men aged 25–44 years (screening V).*

The sleep self-assessment distribution of VNTR carriers of *DRD4* gene polymorphism is presented in **Table 6**. Carriers of genotype 2/4 of the *DRD4* gene were more likely to respond that their sleep was "good" (16.2%) than "satisfactory" (7.9%), both compared with carriers of all other genotypes (χ<sup>2</sup> = 5.626 υ =1p < 0.01) and compared with carriers of genotype 4/4 (χ<sup>2</sup> = 4.507 υ =1p < 0.05). Self-assessment of sleep as "poor/good" revealed a significant difference between carriers of genotypes 2/4 and 4/6; in the former, self-assessment of sleep as "good" predominated (16.2%), and the latter more often assessed their sleep as "poor" (28.6%) (χ<sup>2</sup> = 5.714 df = 1, p < 0.05). For the "good/very good" sleep self-assessment, the "very good" (15.4%) rather than "good" (4.3%) responses were more common among genotype 3/4 carriers (χ<sup>2</sup> = 5.199 υ =1p < 0.05). Among carriers of genotype 4/4, sleep is more often assessed as "satisfactory" (61.8%) than "poor" (38.1%), as in comparison with carriers of all other genotypes (χ<sup>2</sup> = 7.687 υ = 1, p < 0.01), and in comparison with carriers of genotype 4/6 OR = 12.7 (95% CI 4.1–38.7); (χ<sup>2</sup> = 26.941 υ =1p < 0.0001). A reliable result was obtained when comparing carriers of genotype 4/4, in which the score "good sleep" prevails (60%), with carriers of genotype 2/6, in which the score "poor sleep" prevails (7.1%), OR = 10, 4 (95% CI 1.6–67.1); (χ<sup>2</sup> = 8.772 df = 1 p < 0.01). Self-assessment of sleep as "good" (60%) in carriers of genotype 4/4 is more common than assessment as "very good" (40%) among carriers of all other genotypes (χ<sup>2</sup> = 6.664 υ =1p < 0.01) and in comparison with carriers of genotype 2/4 (15.4%) (χ<sup>2</sup> = 5.223 υ =1p < 0.05). Among carriers of genotype 4/6, there is an increase in responses of "poor sleep" (28.6%) rather than "satisfactory" (3.6%) in comparison with carriers of all other genotypes OR = 10.6 (95% CI 3.6–30.4); (χ<sup>2</sup> = 26.217 υ =1p < 0.0001); with carriers of genotype 2/4 OR = 5.2 (95% CI 1.2–21.5); (χ<sup>2</sup> = 5.461 υ =1p < 0.05).

Carriers of allele 2 of the *DRD4* gene more often assessed their sleep as "good" (15.4%) than "poor" (9.5%), in comparison with carriers of all other alleles (χ<sup>2</sup> = 5.739 υ =1p < 0, 01) as well as with carriers of allele 3 (χ<sup>2</sup> = 4.790 υ =1p < 0.05). Carriers of allele 4 were more "satisfied" (71.5%) with their sleep than carriers of all other alleles (χ<sup>2</sup> = 4.101 υ =1p < 0.05). Carriers of allele 5 rated their sleep as "very poor" (7.1%) much more often than "satisfactory" (0.9%), in comparison with carriers of all other alleles OR = 8.3 (95% CI 0.8–86.1); (χ<sup>2</sup> = 4.541 υ =1p < 0.05).
