Janek Spada

Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study

The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep‐related phenotypes, known genetic variants explain only a small proportion of the phenotypical variance. However, most previous studies were based solely upon self‐report measures. The present study aimed to conduct the first genome‐wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle‐ to older‐aged subjects (40–79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night‐ and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P ≤ 5× 10−8 (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 × 10−8). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 × 10−8), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow‐up studies.

Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder

The arousal regulation model of affective disorders attributes an important role in the pathophysiology of affective disorders to dysregulation of brain arousal regulation. According to this model, sensation avoidance and withdrawal in depression and sensation seeking and hyperactivity in mania can be explained as auto‐regulatory attempts to counteract a tonically high (depression) or unstable (mania) arousal. The aim of this study was to compare brain arousal regulation between manic and depressive bipolar patients and healthy controls. We hypothesized that currently depressed patients with bipolar disorder show hyperstable arousal regulation, while currently manic patients show unstable arousal regulation.

Genetic Association of Objective Sleep Phenotypes with a Functional Polymorphism in the Neuropeptide S Receptor Gene

Background The neuropeptide S receptor (NPSR1) and its ligand neuropeptide S (NPS) have received increased attention in the last few years, as both establish a previously unknown system of neuromodulation. Animal research studies have suggested that NPS may be involved in arousal/wakefulness and may also have a crucial role in sleep regulation. The single nucleotide polymorphism (SNP) rs324981 in NPSR1 has begun to shed light on a function of the NPS-system in human sleep regulation. Due to an amino acid exchange, the T-allele leads to an increased sensitivity of the NPSR1. In the only genome-wide association study to date on circadian sleep parameters in humans, an association was found between rs324981 and regular bedtime. However, the sleep parameters in this study were only measured by self-rating. Therefore, our study aimed to replicate these findings using an objective measure of sleep. Methods The study included n = 393 white subjects (62–79 years) who participated in an actigraphic assessment for determining sleep duration, rest duration, sleep onset, rest onset and sleep onset latency. Genotyping of the SNP rs324981 was performed using the TaqMan OpenArray System. Results The genotype at rs324981 was not significantly associated with rest onset (bedtime) or sleep onset (p = .146 and p = .199, respectively). However, the SNP showed a significant effect on sleep- and rest duration (p = .007 and p = .003, respectively). Subjects that were homozygous for the minor T-allele had a significantly decreased sleep- and rest duration compared to A-allele carriers. Conclusion The results of this study indicate that the sleep pattern in humans is influenced by the NPS-system. However, the previously reported association between bedtime and rs324981 could not be confirmed. The current finding of decreased sleep duration in T/T allele carriers is in accordance with studies in rodents reporting similar results after NPS application.

Sleep disturbances and upregulation of brain arousal during daytime in depressed versus non-depressed elderly subjects

Abstract Objectives: Although patients with depression often suffer from sleep disturbances, most of them are not sleepy. Upregulation of brain arousal has been proposed as pathophysiological mechanism explaining sleep disturbances, inner tension, autonomic hyperarousal and anhedonia in depression. The aim of the current study was to examine the association between night-time sleep disturbances and brain arousal regulation the next day in depressed versus non-depressed subjects. Methods: Twenty-eight elderly subjects (21 female; age = 70.5 ± 4.4 years) with depressive syndromes without psychotropic medication, and 28 controls (22 female; age = 70.9 ± 4.5 years), underwent a 15-min resting electroencephalogram; the Vigilance Algorithm Leipzig (VIGALL 2.1) provided an objective measure of brain arousal regulation. Sleep disturbances were assessed by a validated and self-rated sleep questionnaire. Results: In the depressive group, but not in controls, more sleep disturbances were associated with a higher brain arousal stability score (high score corresponds to upregulation) the next day (sleep onset latency: rs = 0.69, P < .0001; sleep quality: rs = −0.59, P < .001). Conclusions: The data confirm the hypothesis that in persons with depressive syndromes sleep disturbances are related to upregulation of brain arousal the next day. This finding is in line with the concept that dysregulation of brain arousal is a central pathophysiological aspect in depression.

Time to wake up: No impact of COMT Val158Met gene variation on circadian preferences, arousal regulation and sleep

ABSTRACT Dopamine has been implicated in the regulation of sleep–wake states and the circadian rhythm. However, there is no consensus on the impact of two established dopaminergic gene variants: the catechol-O-methyltransferase Val158Met (COMT Val158Met; rs4680) and the dopamine D4 receptor Exon III variable-number-of-tandem-repeat polymorphism (DRD4 VNTR). Pursuing a multi-method approach, we examined their potential effects on circadian preferences, arousal regulation and sleep. Subjects underwent a 7-day actigraphy assessment (SenseWear Pro3), a 20-minute resting EEG (analyzed using VIGALL 2.0) and a body mass index (BMI) assessment. Further, they completed the Morningness–Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). The sample comprised 4625 subjects (19–82 years) genotyped for COMT Val158Met, and 689 elderly subjects (64–82 years) genotyped for DRD4 VNTR. The number of subjects varied across phenotypes. Power calculations revealed a minimum required phenotypic variance explained by genotype ranging between 0.5% and 1.5% for COMT Val158Met and between 3.3% and 6.0% for DRD4 VNTR. Analyses did not reveal significant genotype effects on MEQ, ESS, PSQI, BMI, actigraphy and EEG variables. Additionally, we found no compelling evidence in sex- and age-stratified subsamples. Few associations surpassed the threshold of nominal significance (p < .05), providing some indication for a link between DRD4 VNTR and daytime sleepiness. Taken together, in light of the statistical power obtained in the present study, our data particularly suggest no impact of the COMT Val158Met polymorphism on circadian preferences, arousal regulation and sleep. The suggestive link between DRD4 VNTR and daytime sleepiness, on the other hand, might be worth investigation in a sample enriched with younger adults.

Evoked potentials and behavioral performance during different states of brain arousal

BackgroundPrevious studies compared evoked potentials (EPs) between several sleep stages but only one uniform wake state. However, using electroencephalography (EEG), several arousal states can be distinguished before sleep onset. Recently, the Vigilance Algorithm Leipzig (VIGALL 2.0) has been developed, which automatically attributes one out of seven EEG-vigilance stages to each 1-s EEG segment, ranging from stage 0 (associated with cognitively active wakefulness), to stages A1, A2 and A3 (associated with relaxed wakefulness), to stages B1 and B2/3 (associated with drowsiness) up to stage C (indicating sleep onset). Applying VIGALL, we specified the effects of these finely differentiated EEG-vigilance stages (indicating arousal states) on EPs (P1, N1, P2, N300, MMN and P3) and behavioral performance. Subjects underwent an ignored and attended condition of a 2-h eyes-closed oddball-task. Final analysis included 43 subjects in the ignored and 51 subjects in the attended condition. First, the effect of brain arousal states on EPs and performance parameters were analyzed between EEG-vigilance stages A (i.e. A1, A2 and A3 combined), B1 and B2/3&C (i.e. B2/3 and C combined). Then, in a second step, the effects of the finely differentiated EEG-vigilance stages were further specified.ResultsComparing stages A versus B1 versus B2/3&C, a significant effect of EEG-vigilance stages on all behavioral parameters and all EPs, with exception of MMN and P3, was found. By applying VIGALL, a more detailed view of arousal effects on EP and performance was possible, such as the finding that the P2 showed no further significant increase in stages deeper than B1. Stage 0 did not differ from any of the A-stages. Within more fine-graded stages, such as the A-substages, EPs and performance only partially differed. However, these analyses were partly based on small sample sizes and future studies should take effort to get enough epochs of rare stages (such as A3 and C).ConclusionsA clear impact of arousal on EPs and behavioral performance was obtained, which emphasize the necessity to consider arousal effects when interpreting EPs.

Human brain arousal in the resting state: a genome-wide association study

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

P135. EEG-based assessment of wakefulness regulation in different mood states in bipolar disorder – A retrospective analysis

Background According to the vigilance theory of affective disorders, unipolar depression is characterised by a hyperstable wakefulness regulation, meaning that patients suffering from depression show a high alertness and a less distinct and later decline into lower vigilance and sleep states. Mania on the other hand is associated with an unstable wakefulness regulation with a rapid decline into sleep states and quickly alternating wakefulness states ( Hegerl and Hensch, 2012 ). This theory has been backed up for unipolar depression in recent years ( Hegerl et al., 2012 ). However, so far EEG-based assessment of wakefulness regulation has not been performed for bipolar patients in different mood states. Objective The aim of this study is to assess and to compare wakefulness regulation in bipolar depression, mania and euthymia. This will be done both for diagnostic groups as well as for individual patients for whom EEG-recordings in all mood states are available. Methods This is going to be a retrospective, cross-sectional analysis. In the department of psychiatry at the university hospital in Leipzig, inpatients suffering from bipolar mania/depression and bipolar outpatients in euthymia undergo a 15-min resting EEG. Strict inclusion and exclusion criteria were defined to ensure comparability of results. So far, we have included 23 manic, 13 hypomanic and 51 depressive patients suffering from bipolar disorder. Mood at the time of EEG-recording is assessed via the Young Mania Rating Scale (YMRS) and the 17-item Hamilton rating scale for depression (HAMD-17). EEG-vigilance regulation will be determined with a computer-based vigilance classification algorithm (VIGALL, Vigilance Algorithm Leipzig), allowing a classification of vigilance stages A (with substages A1, A2 and A3), B (with substages B1 and B2/3) and C. Hypothesis We hypothesize that currently depressive bipolar patients will show hyperstable wakefulness, while currently manic patients will show an unstable wakefulness regulation. Furthermore, we hypothesize that this is a state – rather than a trait – dependent regulation.