Journal of Sleep Disorders: Treatment and CareISSN: 2325-9639

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Research Article, J Sleep Disor Treat Care Vol: 4 Issue: 2

Association between Sleep Duration and Personality-Gene Variants: Sleep Duration is Longer in S/S Homozygotes of Serotonin Transporter than in L Allele Genotypes

Akiko Koga1, Akiko Fukushima2, Keiko Sakuma2 and Yasuo Kagawa1*
1Department of Medical Chemistry, Kagawa Nutrition University, Japan
2Department of Molecular Nutrition, Kagawa Nutrition University, Japan
Corresponding author : Yasuo Kagawa, Ph.D
Department of Medical Chemistry, Kagawa Nutrition University, 3-9-21 Chiyoda, Sakado City, Saitama, 350-0288, Japan
Tel: +81 (49) 282 3618; Fax: +81 (49) 282 3618
E-mail: [email protected]
Received: February 10, 2015 Accepted: June 30, 2015 Published: July 03, 2015
Citation: Koga A, Fukushima A, Sakuma K, Kagawa Y (2015) Association between Sleep Duration and Personality-Gene Variants: Sleep Duration is Longer in S/S Homozygotes of Serotonin Transporter than in L Allele Genotypes. J Sleep Disor: Treat Care 4:2. doi:10.4172/2325-9639.1000156


Heavy Issue: Clarifying AHI Elevation after Contemporary Airway Surgery for OSA – The MACHO Graph

Objective: Personality genes and lifestyle and depression scores of young women were analyzed to reevaluate conflicting findings regarding the relationship between worry and sleep schedule (sleep duration, bedtime etc.).
Methods: Genes encoding serotonin transporter (5-HTT; S/S, S/L, L/L, and S/XL genotypes) and dopamine D4 receptor (DRD4; 2/4, 4/4, and other genotypes) and three clock genes were genotyped for 42 healthy female Japanese students (age range: 20-21). Their mood was assessed via the Center for Epidemiologic Studies Depression Scale (CES-D). Their personalities were assessed via the NEO Five-Factor Inventory (NEO-FFI). They maintained a diary and completed a questionnaire about sleep and dietary intake.
Results: The variant frequencies for S/S homozygote of 5-HTT and 4/4 homozygote of DRD4 were higher among this group than among Caucasians. Sleep duration was 40.8 min longer (7.13 ± .94 hrs) in 5-HTT S/S homozygotes than in others (6.45 ± .69
hrs) (p=0.018), and the bedtime was earlier (0:16 ± 1:05 h:min) for 5-HTT S/S homozygotes than for L allele genotypes (1:14 ± 0:41 h:min) (p=0.005). A “delayed bedtime phenotype” was evident in 55% of S/S homozygotes and 100% of L allele-bearing individuals. Sleep duration was also 42.0 min longer in 4/4 homozygotes (7.09 ± 0.94 hrs) of DRD4 than that in 4/2 heterozygotes (6.39 ± .77 hrs) (p=0.042). An inverse correlation (r=-.316, p=.043) between ppppsleep duration and CES-D score was detected. When groups with high and low CES-D scores were compared, “Delayed bedtime phenotypes”, Neuroticism, and Conscientiousness of NEO-FFI were 100%:59.3%, 34.0:25.5, and 24.6:28.2, respectively.
Conclusion: Both stress-susceptible genotypes, S/S homozygotes of 5-HTT and 4/4 homozygotes of DRD4, slept longer than genotypes with the L-allele of 5-HTT, and 4/2 heterozygotes of DRD4, respectively. The high CES-D group comprised short
sleepers, irrespective of genotype.

Keywords: Sleep duration; Delayed bedtime phenotype; Serotonin transporter; Dopamine D4 receptor; Genetic polymorphism; CES-D score; NEO-FFI


Sleep duration; Delayed bedtime phenotype; Serotonin transporter; Dopamine D4 receptor; Genetic polymorphism; CES-D score; NEO-FFI


5-HTT: Serotonin Transporter Gene; BDHQ: Brieftype Self-Administered Diet History Questionnaire; CESD: Center for Epidemiologic Studies Depression Scale; DRD4: Dopamine D4 Receptor Gene; MRI: Magnetic Resonance Imaging; VNTR: Variable Number Tandem Repeat


Sleep disturbances are commonly reported in both normal and psychiatric populations. There are considerable individual differences in sleep duration, and individuals with anxiety and worry are reported to be long sleepers [1,2], depending on anxiety levels [3]. Previous studies have focused on personality differences between naturally short sleepers and naturally longer sleepers [1,2]. However, there have been conflicting reports on the relationship between sleep duration and worry or anxiety. Reportedly, anxiety is related to sleep in a U-shaped curvilinear fashion [2].
Anxiety disorders are reportedly partially genetically controlled by allelic variants of both serotonergic and dopaminergic genes [4,5]. Both independent and interacting effects of polymorphisms of two serotonin transporter genes (5-HTT; SLC6A4) [5,6] and dopamine D4 receptor (DRD4) [7] on stress responsivity (as reflected by cortisol levels) have also been reported [5]. These are closely related to personality and depression [4,5]. A polymorphism (short allele=S and long allele=L) in the 5’ regulatory region of the serotonin transporter gene (5-HTT linked polymorphic region; 5-HTTLPR in SLC6A4) reportedly influences depression [6]. Subjects who are S/S (homozygous for the short allele of 5-HTTLPR) are three times more likely to be depressed in response to stressful life events than subjects who are L/L homozygotes [6], who are resistant to stress as judged by cortisol secretion [5]. In addition, persons with a 4/4 genotype (homozygous for the 4-repeat allele) are also reported to be susceptible to stress [5,7]; in contrast, carriers of 7-repeat allele of DRD4 are reported to be resistant to stress [5]. Since ethnic difference in behavior may be caused by variation in frequencies of depression-susceptible alleles, we genotyped these genes and found that the frequency of the S/S genotype of 5-HTT was 69.3% among Japanese [8]; this frequency is 4.3-fold higher than that among Caucasians (16%) [9]. Functional magnetic resonance imaging (fMRI) confirmed the mechanisms of anxiety and worry involved the amygdala and genetic polymorphism of 5-HTT [9]. Amygdala activity is greater in 5-HTT S-allele carriers than in 5-HTT L-allele carriers; this finding is consistent with the amygdala response being crucial in depression-related temperament traits [9]. Meta-analysis of psychiatric tests including Center for Epidemiologic Studies Depression Scale (CES-D) indicates that the polymorphisms of 5-HTT [4-6,8, 9] and DRD4 [5,7,8] have a reliable influence on depression and personality [10], both of which are closely related to anxiety [4,5,10]. Environmental influences on personality are minimal in neonates, yet polymorphisms of both DRD4 and 5-HTT affect neonatal temperament [11]. Genetic polymorphisms of clock genes have been correlated to sleep disturbance [12]. Thus, we analyzed single nucleotide polymorphisms (SNPs) of CLOCK and PER with large minor allele frequencies [12].
Particular personality traits are associated with enhanced worry, which may contribute to difficulties falling asleep [13]. Thus, in addition to the genotype analyses, we used CES-D to estimate depressive mood [14,15] and the NEO-FFI (Five-Factor Inventory) to evaluate personality, including Neuroticism and Conscientiousness [16]; we then analyzed the effects of personal difference on sleep quantity (duration) and sleep schedule (waking and bedtime).
The circadian rhythm of the peripheral clock gene is known to be reset by diet [17]. Specifically, normal sleep duration was reported to be associated with the greatest food variety, compared to very short, short, and long sleep duration (p<0.001), and significant associations between sleep duration were found across nutrient categories (proteins, carbohydrates, vitamins, and minerals) [18]. Therefore, we assessed meal time and dietary intake of the subjects.
In the course of our study, Carskadon and colleagues reported that stressed first-year students who reported shorter nocturnal sleep and moods that are more depressed are more likely than others to be S/S homozygotes [19]. In this report, we measured sleeping habits and the CES-D scores of third-year female Japanese university students and found that 5-HTT S/S homozygotes and DRD4 4/4 homozygotes slept longer than those with L allele of 5-HTT and 4/2 heterozygotes of DRD4, respectively. Subjects with higher CES-D scores, however, were shorter sleepers, and their average bedtime was later than that of those with lower CES-D scores, irrespective of genotype.


Young healthy female Japanese students from one university (n=42; mean age: 20 years, range: 20-21) were recruited. They all had normal blood-chemistry profiles, and none were using special medication. Subject characteristics are grouped by 5-HTT genotype in Table 1. The subjects generally had adequate time to sleep because of the late school start time (9:20) and early ending time (16:30). Their individual curriculums were nearly all equal, and they were accustomed to school life after three years of attending university. The study was carried out in accordance with the Declaration of Helsinki; the Kagawa Nutrition University Human Subjects and Genome Ethics Committee (No. 135G) approved study procedures; written informed consent was obtained from each subject.
Table 1: Demographics including Sleep duration, CES-D score, and daily life rhythm for each serotonin transporter genotype group.
Sample collection, genotyping, and biochemical analyses
Venous blood samples were collected in plain and EDTAcontaining Venoject tubes from each subject before breakfast. The MagtrationTM System device (Precision Systems Science Co. Ltd., Chiba, Japan) was used with magnetic particles to extract and purify genomic DNA from each whole-blood sample [20]. As described in detail in a previous report [8], polymorphisms of 5-HTT and of the DRD4 exon III variable number tandem repeat (VNTR) were genotyped by the methods of Lesch et al. [21] and Ono et al. [22], respectively. SNP typing of CLOCK (c.*213T>C: rs1801260) [12], CLOCK (5'upstream AG: rs4864548) [10], and PERIOD (PER2 5'UTR CG: rs2304672) [12] were performed with a TaqMan genotyping system and an ABI PRISM 7900HT unit (Applied Biosystems, Foster City, CA) in the Division of Human Genetics Center for Community Medicine, Jichi Medical University.
Self-reports of sleep and daily habits
Self-report methods were used to assess daily habits and difficulty in initiating or maintaining sleep. Diaries of sleep duration and quality for 1 week and daily habits were available for subjects to complete each day from early evening until early the next morning. Sleep schedule (i.e., average waking and bedtime) and sleep quantity (duration) were reported in the detailed diary. The reported sleep duration was averaged for one week, and the coefficient of variation (CV=standard deviation/mean × 100) was calculated. A “Delayed bedtime phenotype” was defined as one who started to sleep later than 0 o’clock. Their academic performance was evaluated by their score on a simulation test of the national examination for registered dietitians.
Depressive symptoms and personality assessment
The primary mood outcome measure used was depressive symptoms, which were assessed via the Japanese version [14] of the CES-D scale [15]. This scale consists of 20 questions that address six symptoms of depression: depressed mood, guilt or worthlessness, helplessness or hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance [14,15]. Each question is scored on a scale of 0 to 3, and the total CES-D score ranges from 0 to 60. Depressive symptoms were defined as present when a subject had a CES-D score of 16 or more. The criterion validity of the scale is well established both in Japan [14] and Western countries [15]. For evaluation of personality, the NEO-FFI (NEO-five factor inventory) was used according to the method reported by Weiss et al. [16].
Dietary intake
Dietary intake was assessed using a validated, brief-type, selfadministered diet history questionnaire (BDHQ) [23] that contains questions about the consumption frequency of 56 foods and beverages commonly consumed by the Japanese population. Energy and nutrient intake were estimated using an ad hoc computer algorithm for the BDHQ [23]. The validation study of the BDHQ, using 16-d weighted dietary records as a standard, revealed that Pearson’s correlation coefficients for folate intake in women were 0.62 [23]. Anthropometric data were determined as reported previously [8].

Statistical Analyses

In the comparison of genotype groups, one subject with the 5-HTT S/XL genotype was excluded, and the nine subjects with genotypes other than DRD4 4/4 or DRD4 4/2 were excluded. For statistical analyses, the Mann–Whitney U test was performed using Stat View version 5.0 (SAS Institute Inc., Cary, NC, USA) or SPSS Statistics 17.0 (IBM Japan, Ltd., Tokyo, Japan). This test is a nonparametric test of the null hypothesis (that two samples come from the same population) against an alternative hypothesis. We considered p values of <.05 statistically significant.


Genotype frequencies
The frequencies of the 5-HTT genotypes (S/S, S/L, L/L, and S/XL) were 64.3% (n=27), 31.0% (n=13), 2.4% (n=1), and 2.4% (n=1), respectively, and the frequency of the S allele was 81.0%. The frequencies of the DRD4 genotypes (4/2, 4/4, and “other”) were 23.8% (n=10), 54.8% (n=23), and 21.4% (n=9), respectively. The 4/4 homozygous genotype was predominant in this Japanese population. These genotype and allele frequencies for 5-HTT and DRD4 were similar to those reported previously for 264 Japanese women [8]. The frequencies of the CLOCK c.*213T>C genotypes (T/T, T/C, and C/C) were 64.3% (n=27), 33.3% (n=14), and 2.4% (n=1), respectively. The frequencies of the CLOCK 5’ upstream A/G site (A/A, A/G, and G/G) were 28.6% (n=12), 35.7% (n=15), and 35.7% (n=15), respectively. The frequencies of the PER2 5’ UTR C/G genotypes (C/C and G/C) were 85.7% (n=36) and 14.3% (n=6), respectively. These varying frequencies were similar to that of our parallel survey on 836 Japanese (data not shown).
Daily rhythms of the subjects
The reported characteristics of the daily rhythms of the study subjects were based on their self-report on sleep duration, timing of meals, and sleep habits and are presented in Table 1. The average duration of sleep (6.90 hrs) (Table 1) was longer than that of Asians (less than 5 hrs) [24] and working Japanese women (6.47 hrs) [25]. The average sleep duration of a longer sleeper reported here is 7.13 hrs, while that of a short sleeper is 6.45 hrs (Table 1); these durations are similar to those in Carskadon’s report [19].
Bedtime depending on genotypes
Bedtime of 5-HTT S/S homozygotes was 58 min earlier than that of subjects with an L allele (p<.005) (Table 1). On the other hand, 100% of subjects with the L allele were classified as “Delayed bedtime phenotype” (bedtime later than 0 o’clock), but only 55.56% of S/S homozygotes were “Delayed bedtime phenotype” (p<.021) (Table 1). However, total eating time for breakfast, lunch, and dinner; waking time; sleep onset latency; and days using a personal computer, television, or telephone 1 hour before bedtime were not significantly different between S/S and S/L+L/L groups (Table 1).
Sleep duration and genotypes
Sleep duration was .68 hrs (40.8 min) longer for 5-HTT S/S homozygotes than for those with L allele genotypes (p=.018) (Table 1). Sleep duration was also .70 hrs (42.0 min) longer for DRD4 4/4 homozygotes than for DRD4 4/2 heterozygotes (p=.042) (Table 2). CES-D scale scores did not differ between two groups of different alleles of 5-HTT and DRD4 (Table 1 and 2). Additionally, CV for sleep duration did not reach significant levels even in CLOCK c.*213T>C genotypes (p=.08). Sleep duration, bedtime, and waking time were each not significantly different among genotypes of CLOCK (rs1801260), CLOCK 5’ upstream (rs4864548), or PER2 5’UTR. Bedtime, but not waking time, was significantly earlier (0:16 ± 1:05 h:min) among 5-HTT S/S homozygotes than (1:14 ± 0:41 h:min) among those with the 5-HTT L allele (p=.005); 55% of 5-HTT S/S homozygote went to sleep after 0 o’clock; in contrast, 100% of those with a 5-HTT L genotype did (Table 1).
Table 2: Sleep duration and CES-D scale of dopamine D4 receptor genotype groups.
Correlations among bedtime, sleep duration, and CES-D score
A significant inverse correlation between sleep duration and CES-D score was detected (Figure 1A, r=-.316, p=.043). On average, the bedtime scores were 54 min later for subjects with high CES-D scores than for those with low CES-D scores (p=.016) (Table 3). All subjects with a high CES-D score (cut-off point 16) showed the “Delayed bedtime phenotype”, while only 59.25% of those with low CES-D did (p=.021) (Table 3). On average, sleep duration was 0.53 hrs (31.8 min) shorter for subjects with high CES-D score than for those with low CES-D scores, and the difference did not reach a significant level (p=.070) (Table 3). It was also important to note that subjects with high CES-D score felt waking time to be unpleasant more often than did those with low CES-D scores (p=.001) (Table 3). However, total eating time for breakfast, lunch, and dinner; waking time; sleep onset latency; or days using a personal computer, television, or telephone 1 hour before bedtime were not different between the two CES-D groups (Table 3). A scatter plot and regression line of bedtime and sleep duration also revealed a strong inverse correlation (r=- .648, p<.001) (Figure 1B); CES-D score was positively correlated with bedtime (r=.441, p=.005) (Figure 1C).
Table 3: CES-D group demographics including sleep duration and daily life rhythm.
Figure 1: Relationships between sleep duration and CES-D scale (A), bedtime and sleep duration (B), bedtime and CES-D score (C), and NEO-FFI Neuroticism score and CES-D score (D).
CES-D scores and NEO FFI
Subjects with high CES-D scores showed higher Neuroticism scores (p=.001), while those with low CES-D scores showed higher Conscientiousness scores (p=.048) (Table 4). The positive correlation between CES-D score and Neuroticism score is shown in Figure 1D (r=.591, p<.001). The difference in scores representing Extraversion, Openness, and Agreeableness between both CES-D groups did not reach the significance level (Table 4).
Table 4: CES-D group demographics including NEO-FFI tests.
NEO-FFI scores and genotypes
The results of the NEO-FFI test for subjects with genotypes of 5-HTT and DRD4 are summarized in Tables 5 and 6, respectively. The score of Extraversion was greater among 5-HTT S/S homozygotes than among those with L/S or L/L genotypes (p=.031) (Table 5). The score of Conscientiousness was lower among 4/4 homozygotes than among 4/2 heterozygotes (p=.009) (Table 6). However, the differences of scores in Neuroticism, Openness, and Agreeableness were not significant between the genotypes tested (Tables 5 and 6).
Table 5: NEO-FFI tests results for serotonin transporter genotype groups.
Table 6: NEO-FFI tests for dopamine D4 receptor genotype groups.
Dietary intake and meal times
There were no significant differences in food and nutrient intake between genotype groups. Meal times were also not significantly different between the groups examined (Table 1).


In order to clarify conflicting findings regarding the relationship between anxiety and length of sleep [1-3], we analyzed two anxiety-associated genetic polymorphisms of 5-HTT [4-6,8,9] and DRD4 [4,7,8,11]. The serotonin neurotransmitter system is a central actor in depression, most notably in depression pharmacotherapy, which features drugs that affect serotonin reuptake [26]. The pharmacological treatment of neuropsychiatric diseases with dopaminergic drugs [27] is related to mood disorders depending on DRD4 polymorphism [7].
Our findings indicate that third-year female university students who carry the S/S genotype show longer nocturnal sleep than those who carry the L/S or L/L genotype (Table 1). The longer sleep duration of S/S homozygotes was mainly caused by their 58 min earlier bedtime than that of subjects with L allele (p<.005) (Table 1). Notably, 100% of subjects with L allele were classified as “Delayed bedtime phenotype”, but only 55.56% of S/S homozygotes were “Delayed bedtime phenotype” (p<.021) (Table 1). The difference of sleep duration between students in our study (7.13 hrs) (Table 1) and working Japanese women (6 hrs 28 min) [25] may be caused by their different leisure time: students’ late school start time vs. women’s busy housekeeping and work.
The genetic and mood analysis supports previous reports that worry and anxiety and length of sleep were positively correlated [1,2] because anxiety and worry were substantially correlated (r=.60) for certain subjects [3]. In contrast to our findings, a recent report [19] concluded that first-year university students who carry the 5-HTT S/S genotype report short nocturnal sleep together with depressed mood caused by stress of a new school environment. The long sleep duration of S/S homozygotes of the third-year students in this study might have prevented depressed mood, while short sleep duration, which was irrespective of genotype, resulted in a more depressed mood (Figure 1A). An inverse correlation between sleep duration and CES-D score was detected (Figure 1A), suggesting depressed mood results in shorter sleep duration.
When compared to those with low CES-D scores, subjects with high CES-D scores showed significantly higher NEO-FFI Neuroticism scores (Table 4, p<.001), a 54-min later bedtime (Table 3, p=.016), and a tendency for shorter sleep duration (Figure 1A, r=-.316, p=.043). Reportedly, neuroticism significantly mediates the risk of insomnia of college students with a mean age of 18.9 ± 2.1 yrs [28]. The neuroticism domain scale assesses the degree of negative affectivity and comprises facets such as anxiety and depression, leading to insomnia [13].
Compared with those with high CES-D scores, subjects with low CES-D scores showed significantly higher NEO-FFI Conscientiousness scores (Table 4, p=.048), longer sleep duration (Figure 1A, r=-.316, p=.043), and an earlier bedtime (Table 3). A positive correlation between CES-D score and NEO-FFI Conscientiousness score (Figure 1D, r=.591, p<.001) indicated a tight relationship among mood, personality, and sleep schedule (i.e., average waking and bedtime). In fact, sleep schedules are reportedly significantly related to NEO-FFI Conscientiousness scores [29].
In summary, subjects with high CES-D scores showed higher scores on Neuroticism (p=.001) and lower Conscientiousness (p=.048) than individuals with low CES-D (Table 4). Those with high CES-D score also showed shorter sleep duration (Figure 1A) and later bedtimes (Table 3). Similarly, it was reported that those who reported trouble falling asleep showed higher scores on Neuroticism (p=.013) and lower scores on Conscientiousness (p=.014) than individuals who did not have sleep initiation difficulties [13].
Disturbed sleep can precede, follow, or co-occur with depressed mood measured with CES-D [30]. To solve a part of this complicated interplay between insomnia and depression, the reliability of the CES-D was confirmed by removing one sleep-related item from the CES-D questionnaire list, because the measure of depressed mood was not affected by the removal [31]. Our results and those of Carskadon [19] on sleep schedule are similar when CES-D score is compared, but different if 5-HTT genotype is compared. Sleep schedule was reported to be directly affected by CES-D score and is indirectly affected only when 5-HTT genotypes induce CES-D score reduction in the case of stressed first-year students [19]. Genotype is invariable, but CES-D scores can be improved. In fact, after the instruction to the subjects with high academic performance to follow their regular lifestyle, CES-D scores were significantly improved from 13.5 ± 8.1 to 8.9 ± 7.6 (p=.048) irrespective of genotypes, and all subjects passed the national accreditation examination for registered dietitians. The definition of optimal sleep quantity and quality is a controversial issue [32], but the average of 7 hrs of sleep is the best to minimize the mortality hazard ratio of approximately one million subjects from 30 to 102 years of age [33]. This optimal sleep duration is supported by the fact that 7 hrs of sleep also minimizes the incidence of diabetes, hypertension, and obesity [34]. However, these reports are based on the averages of populations surveyed, and the average does not imply optimal sleep duration and quality for each individual who has different genetic polymorphisms studied here.


Our findings should be considered in light of several limitations. An obvious limitation of the present study is that only two personality genes (5-HTT and DRD4) and three clock genes were analyzed. The reason why clock gene variants that are known to affect sleep schedule [12,17,35] did not show significant effects among our subjects remains to be elucidated. Second, the subjects studied were young women, and the effects of the variables in older individuals and men were not examined. A third limitation was the lack of electro-encephalographic and other objective assessments [17]; subjective assessment of sleep duration can be biased and does not provide insight into how long an individual actually sleeps. A fourth limitation is the lack of neuroimaging [17] including functional MRI (fMRI) tests of the amygdala to substantiate the relationship between worry and genetic polymorphism [9]. A fifth limitation was the lack of combination data comprising the eight 5-HTT and DRD4 genotypes due to low statistical power caused by the small sample number and rare variant frequencies; thus a larger study sample is needed. A sixth limitation was the omission of other candidate genes for sleep disturbances [17], including the gene KLF6 (rs2031573) and PCDH7 (rs1037079) found by the genome wide association studies (GWAS) of the risk alleles for shorter sleep [34-36]. A seventh limitation was that this study did not correct for multiple comparisons; therefore, there may be a great chance of false positive results. Nonetheless, with appropriate appreciation of the aforementioned limitations, the present findings may provide additional insight into the potential contribution of personality genes in sleep difficulties.


Individuals homozygous for S/S of 5-HTT or 4/4 of DRD4 reported longer sleep durations and being able to initiate sleep at earlier times of the day. This observation is perhaps due to differences in the circadian system [17]. However, when a stressful environment increased CES-D or Neuroticism scores, S/S or 4/4 homozygotes may be forced to become “short sleepers”. The effect of common variants of clock genes on sleep schedule [12,17,34] was less evident.


We thank the 42 participants in the survey for their cooperation. The authors’ responsibilities were as follows: AK was responsible for recruiting subjects, and he conceived and designed the study and participated in the statistical analysis. AF and KS genotyped the 5-HTT and DRD4 genes. AK and YK designed the research. YK participated in the overall planning of this research and supervised the acquisition of blood samples and the genotyping as a medical doctor, and he was responsible for drafting the article. The authors report no conflicts of interest with respect to this study.


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