The effect of fragmented sleep on emotion regulation ability and usage.

Sleep has a profound effect on our mood, but insight in the mechanisms underlying this association is still lacking. We tested whether emotion regulation is a mediator in the relationship between fragmented sleep and mood disturbance. The effect of fragmented sleep on the emotion regulation strategies, including cognitive reappraisal, distraction, acceptance and suppression ability, was assessed. We further tested whether the use of these strategies, as well as rumination and self-criticism, mediated the association between fragmented sleep and negative and positive affect. Participants (N = 69) wore an actiwatch and filled in a sleep diary for 12 consecutive nights. They had one control night and one sleep fragmentation night. Emotion regulation ability was assessed with an experimental task. Usage of emotion regulation strategies and negative and positive affect were assessed four times during the day with a survey after the control and sleep fragmentation night. Cognitive reappraisal, distraction, acceptance and suppression ability did not differ between the sleep fragmentation and control condition. However, participants reported higher usage of rumination and distraction after the sleep fragmentation night and rumination significantly mediated the negative association between fragmented sleep and negative affect.

A Genetic Investigation of the Well-Being Spectrum.

The interrelations among well-being, neuroticism, and depression can be captured in a so-called well-being spectrum (3-phenotype well-being spectrum, 3-WBS). Several other human traits are likely linked to the 3-WBS. In the present study, we investigate how the 3-WBS can be expanded. First, we constructed polygenic risk scores for the 3-WBS and used this score to predict a series of traits that have been associated with well-being in the literature. We included information on loneliness, big five personality traits, self-rated health, and flourishing. The 3-WBS polygenic score predicted all the original 3-WBS traits and additionally loneliness, self-rated health, and extraversion (R2 between 0.62% and 1.58%). Next, using LD score regression, we calculated genetic correlations between the 3-WBS and the traits of interest. From all candidate traits, loneliness and self-rated health were found to have the strongest genetic correlations (rg = - 0.79, and rg= 0.64, respectively) with the 3-WBS. Lastly, we use Genomic SEM to investigate the factor structure of the proposed spectrum. The best model fit was obtained for a two-factor model including the 5-WBS traits, with two highly correlated factors representing the negative- and positive end of the spectrum. Based on these analyses we propose to include loneliness and self-rated health in the WBS and use a 5-phenotype well-being spectrum in future studies to gain more insight into the determinants of human well-being.

Correction to: A Genetic Investigation of the Well-Being Spectrum.

In the original version of this article, unfortunately, in the acknowledgement section "National Institutes of Health (NIH, R37 AG033590-08) to J Cacioppo" was omitted. This has been corrected by publishing this erratum.

Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis.

By running gene and pathway analyses for several smoking behaviours in the Tobacco and Genetics Consortium (TAG) sample of 74 053 individuals, 21 genes and several chains of biological pathways were implicated. Analyses were carried out using the HYbrid Set-based Test (HYST) as implemented in the Knowledge-based mining system for Genome-wide Genetic studies software. Fifteen genes are novel and were not detected with the single nucleotide polymorphism-based approach in the original TAG analysis. For quantity smoked, 14 genes passed the false discovery rate of 0.05 (corrected for multiple testing), with the top association signal located at the IREB2 gene (P=1.57E-37). Three genomic loci were significantly associated with ever smoked. The top signal is located at the noncoding antisense RNA transcript BDNF-AS (P=6.25E-07) on 11p14. The SLC25A21 gene (P=2.09E-08) yielded the top association signal in the analysis of smoking cessation. The 19q13 noncoding RNA locus exceeded the genome-wide significance in the analysis of age at initiation (P=1.33E-06). Pathways belonging to the Neuronal system pathways, harbouring the nicotinic acetylcholine receptor genes expressing the α (CHRNA 1-9), ß (CHRNB 1-4), γ, δ and ɛ subunits, yielded the smallest P-values in the pathway analysis of the quantity smoked (lowest P=4.90E-42). Additionally, pathways belonging to 'a subway map of cancer pathways' regulating the cell cycle, mitotic DNA replication, axon growth and synaptic plasticity were found significantly enriched for genetic variants in ever smokers relative to never smokers (lowest P=1.61E-07). In addition, these pathways were also significantly associated with the quantity smoked (lowest P=4.28E-17). Our results shed light on one of the world's leading causes of preventable death and open a path to potential therapeutic targets. These results are informative in decoding the biological bases of other disease traits, such as depression and cancers, with which smoking shares genetic vulnerabilities.

Testing Causal Effects of Maternal Smoking During Pregnancy on Offspring's Externalizing and Internalizing Behavior.

Maternal smoking during pregnancy (SDP) is associated with increased risk of externalizing and internalizing behaviors in offspring. Two explanations (not mutually exclusive) for this association are direct causal effects of maternal SDP and the effects of genetic and environmental factors common to parents and offspring which increase smoking as well as problem behaviors. Here, we examined the associations between parental SDP and mother rated offspring externalizing and internalizing behaviors (rated by the Child Behavior Checklist/2-3) at age three in a population-based sample of Dutch twins (N = 15,228 pairs). First, as a greater effect of maternal than of paternal SDP is consistent with a causal effect of maternal SDP, we compared the effects of maternal and paternal SDP. Second, as a beneficial effect of quitting smoking before pregnancy is consistent with the causal effect, we compared the effects of SDP in mothers who quit smoking before pregnancy, and mothers who continued to smoke during pregnancy. All mothers were established smokers before their pregnancy. The results indicated a greater effect of maternal SDP, compared to paternal SDP, for externalizing, aggression, overactive and withdrawn behavior. Quitting smoking was associated with less externalizing, overactive behavior, aggression, and oppositional behavior, but had no effect on internalizing, anxious depression, or withdrawn behavior. We conclude that these results are consistent with a causal, but small, effect of smoking on externalizing problems at age 3. The results do not support a causal effect of maternal SDP on internalizing behaviors.

Chorionicity and Heritability Estimates from Twin Studies: The Prenatal Environment of Twins and Their Resemblance Across a Large Number of Traits.

There are three types of monozygotic (MZ) twins. MZ twins can either share one chorion and one amnion, each twin can have its own amnion, or MZ twins can-like dizygotic twins-each have their own chorion and amnion. Sharing the same chorion may create a more similar/dissimilar prenatal environment and bias heritability estimates, but most twin studies do not distinguish between these three types of MZ twin pairs. The aim of this paper is to investigate the effect of chorion sharing on the similarity within MZ twin pairs for a large number of traits. Information on chorion status was obtained for the Netherlands twin register (NTR) by linkage to the records from the database of the dutch pathological anatomy national automated archive (PALGA). Record linkage was successful for over 9000 pairs. Effect of chorion type was tested by comparing the within-pair similarity between monochorionic (MC) and dichorionic (DC) MZ twins on 66 traits including weight, height, motor milestones, child problem behaviors, cognitive function, wellbeing and personality. For only 10 traits, within-pair similarity differed between MCMZ and DCMZ pairs. For traits influenced by birth weight (e.g. weight and height in young children) we expected that MC twins would be more discordant. This was found for 5 out of 13 measures. When looking at traits where blood supply is important, we saw MCMZ twins to be more concordant than DCMZ's for 3 traits. We conclude that the influence on the MZ twin correlation of the intra-uterine prenatal environment, as measured by sharing a chorion type, is small and limited to a few phenotypes. This implies that the assumption of equal prenatal environment of mono- and DC MZ twins, which characterizes the classical twin design, is largely tenable.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Genetic and environmental influences on the relationship between adult ADHD symptoms and self-reported problem drinking in 6024 Dutch twins.

BACKGROUND: Cross-sectional and longitudinal studies have shown a positive association between attention deficit hyperactivity disorder (ADHD) and problematic alcohol use in adults. To what extent this association is explained by genetic and environmental factors is largely unknown. METHOD: Data on ADHD and alcohol consumption were collected by self-report in 6024 adult Dutch twins. ADHD symptoms were assessed by three subscales of the Conners' Adult ADHD Rating Scales - Self-Report: Screening Version (CAARS-S:SV): inattentiveness, hyperactivity and the ADHD index (ADHD-I). Problem drinking was defined as at least two self-reported alcohol-related problems on the CAGE questionnaire. Structural equation modelling was applied to the bivariate twin data to estimate genetic and environmental influences. RESULTS: Heritability of ADHD symptoms ranged between 32% and 40% and heritability of problem drinking was 50%. The positive correlation between ADHD symptoms and problem drinking was confirmed in this general population sample, with phenotypic correlations between 0.20 and 0.28 and genetic correlations between 0.39 and 0.50. Phenotypic correlations are primarily (61-100%) explained by genetic influences with non-shared environmental influences explaining the remaining covariance. No significant quantitative or qualitative gender differences in covariance structure were found. CONCLUSIONS: This study convincingly shows that ADHD symptoms and problem drinking are moderately but significantly correlated in adults and that genetic correlations are primarily underlying this association. This suggests that early interventions are required to prevent adolescents with ADHD from developing problematic levels of alcohol use. Furthermore, clinicians who treat alcohol-dependent patients should be aware that the patient may have a co-morbid condition of ADHD; integrated interventions are required.

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).

[Early alcohol initiation and increased adult alcohol consumption: cause or indicator?]. / Vroege alcoholinitiatie en verhoogde alcoholconsumptie op volwassen leeftijd; oorzaak of indicator?

BACKGROUND: Early alcohol initiation is strongly associated with increased alcohol consumption and alcohol abuse/dependence in adulthood. The mechanisms that underlie this association are unclear. AIM: To examine whether there is a causal link between early alcohol initiation and later alcohol consumption. METHOD: Survey data were collected from twin pairs (age range 18-80) included in the Netherlands Twin Register (NTR). A discordant twin design was used to examine the origin of the link between early alcohol initiation and adult alcohol consumption. Within monozygotic pairs (82-143 pairs), twins who started drinking early were compared to their brother/sister who started drinking later, on frequency of alcohol use, weekly alcohol consumption, number of alcohol intoxications, excessive drinking, alcohol abuse/-dependence, and hazardous drinking. By drawing comparisons within monozygotic pairs, we were able to control for the effects of genes/shared environment. Additional analyses examined the effects of age, sex, and in-/exclusion of lifelong abstainers. RESULTS: Within monozygotic twin pairs, the twin who had started drinking early did not differ significantly from his/her brother/sister with respect to future alcohol consumption. Results were independent of age, sex, and in-/exclusion of lifelong abstainers. CONCLUSION: Early alcohol initiation did not have significant causal effects on subsequent alcohol consumption in adulthood and may be an indicator of a predisposition for alcohol consumption. Campaigns aimed at raising the minimum age for alcohol initiation will possibly have only a limited effect on adult alcohol consumption.

The sex-specific interaction between food responsiveness and sleep duration explaining body mass index among children.

OBJECTIVE/BACKGROUND: The inverse relationship between sleep duration and body mass index (BMI) has been well established and appears to be stronger among boys than girls. However, less is known about the mechanisms responsible for this sex-specific link. The main aim of the current study was to examine the sex-specific interaction between food responsiveness and sleep duration in explaining BMI among children. This sex-specific moderation will give more insight into a possible underlying food intake mechanism. PATIENTS/METHODS: In total, 206 caregivers filled out questionnaires on child's sleep duration and food responsiveness (49.5% boys; mean age = 9.5 years; standard deviation = 1.4 years). Child's weight and height were measured, after which age- and sex-specific standardized BMI values (referred to as zBMI here) were calculated. Descriptive statistics and regression analysis were conducted. A potential significant three-way interaction was further examined using simple slopes analysis and slope difference tests. RESULTS: A significant inverse correlation was found between sleep duration and zBMI for boys, but not for girls. Moreover, a significant and robust three-way interaction between sex, food responsiveness and sleep duration explaining child's zBMI was found. Slope difference tests indicate that the sleep-BMI slopes only significantly differed between high-food-responsive boys and high-food-responsive girls and between high-food-responsive boys and low-food-responsive boys. CONCLUSIONS: These findings suggest that increased food intake might be a mechanism explaining the inverse sleep-BMI link among boys.

Heritability of polycystic ovary syndrome in a Dutch twin-family study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. There is evidence for a genetic component in PCOS based on familial clustering of cases. OBJECTIVE: In the present study, the heritability of PCOS was estimated. DESIGN/PARTICIPANTS: Data from 1332 monozygotic twins (genetically identical) and 1873 dizygotic twins/singleton sisters of twins (who share on average 50% of their segregating genes) registered with The Netherlands Twin Register were used. PCOS was defined as less than nine menstrual cycles and acne or hirsutism in agreement with the 2003 Rotterdam consensus. RESULTS: Results point to a strong contribution of familial factors to PCOS. The resemblance in monozygotic twin sisters (tetrachoric correlation 0.71) for PCOS was about twice as large as in dizygotic twin and other sisters (tetrachoric correlation 0.38). Univariate analyses point to strong contributions of genetic factors to the variance in PCOS. Next, a trivariate genetic analysis of oligomenorrhea, acne, and hirsutism was carried out. This analysis confirmed that the familial component in PCOS is due to genetic factors. CONCLUSIONS: This study demonstrated a large influence of genetic factors to the pathogenesis of PCOS, justifying the search for susceptibility genes.

Genetic analysis of morningness and eveningness.

We studied the influence of genetic factors on individual differences in morningness-eveningness in a sample of Dutch twin families. Data were collected from adolescent twins (mean age 17.8 yr) and their parents (mean age of fathers 48.0 yr and of mothers 46.0 yr) and a sample of older twins (mean age 46.5 yr). Scores on morningness-eveningness were rated on a 5-point scale. Parents were more morning oriented than their children, and women were more morning oriented than men. With a twin-family study, separation of genetic and environmental influences on variation in morningness-eveningness is possible. Including parents and older twins in the study makes it possible to explore generation differences in these effects. The correlation between monozygotic twins was more than twice the correlation between dizygotic twins. This indicates that genetic effects may not operate in an additive manner. Therefore, a model that included genetic dominance was explored. Biometrical model fitting showed no sex differences for the magnitude of genetic and environmental factors. The total heritability--the sum of additive and nonadditive genetic influences--for morningness-eveningness was 44% for the younger generation and 47% for the older generation. However, the genetic correlation between the generations turned out to be lower than 0.5, suggesting that different genes for morningness-eveningness are expressed in both generations.

Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting.

Twin studies suggest that genetic factors play a substantial role in anorexia nervosa (AN) and self-induced vomiting (SV), a key symptom that is shared among different types of eating disorders (EDs). We investigated the association of 25 single nucleotide polymorphisms (SNPs), capturing 71-91% of the common variance in candidate genes, stathmin (STMN1), serotonin receptor 1D (HTR1D), tryptophan hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF), with AN and EDs characterized by regular SV. The first allele frequencies of all the SNPs were compared between a Dutch case group (182 AN, 149 EDs characterized by SV) and 607 controls. Associations rendering P-values < 0.05 from this initial study were then tested for replication in a meta-analysis with two additional independent ED case-control samples, together providing 887 AN cases, 306 cases with an ED characterized by SV and 1914 controls. A significant effect for the minor C-allele of tryptophan hydroxylase 2 rs1473473 was observed for both AN [odds ratio (OR) = 1.30, 95% CI 1.08-1.57, P < 0.003] and EDs characterized by SV (OR = 1.52, 95% CI 1.28-2.04, P < 0.006). In the combined case group, a dominant effect was observed for rs1473473 (OR = 1.38, 95% CI 1.16-1.64, P < 0.0003). The meta-analysis revealed that the tryptophan hydroxylase 2 polymorphism rs1473473 was associated with a higher risk for AN, EDs characterized by SV and for the combined group.

A new Ig-superfamily member, molluscan defence molecule (MDM) from Lymnaea stagnalis, is down-regulated during parasitosis.

To survive the attacks of the internal defence system (IDS) of their host, parasites have developed various strategies to manipulate the IDS. We present evidence that the avian schistosome parasite Trichobilharzia ocellata affects gene expression in the granular cells, a cell type of the IDS of the intermediate host, the mollusc Lymnaea stagnalis. From a differential screening, a clone was isolated encoding a protein named molluscan defence molecule (MDM), which encompasses five C2-like immunoglobulin (Ig) domains. The protein shares a domain organization and high amino acid sequence identity with hemolin, an Ig-family member of the insect IDS. Interestingly, both MDM and hemolin have highest sequence identity with neural cell adhesion molecules, but lack the typical fibronectin repeats and motifs for membrane anchors. We find that the expression of the MDM gene is gradually down-regulated during the course of parasitosis to approximately 21% compared to the non-parasitized level, 8 weeks post-infection. Based on our findings, we suggest that MDM is involved in the proper function of the Lymnaea IDS, and that down-regulation of MDM is part of the parasite-induced disabling on non-self recognition.

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs.

The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD=3.05) and chromosome 14 (LOD=1.66) for SI and on chromosome 3 (LOD=1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD=1.92) and for NC (LOD=2.29) which may partly explain the overlapping etiological factors for SI and NC.

Netherlands twin family study of anxious depression (NETSAD).

In a longitudinal study of Dutch adolescent and young adult twins, their parents and their siblings, questionnaire data were collected on depression, anxiety and correlated personality traits, such as neuroticism. Data were collected by mailed surveys in 1991, 1993, 1995 and 1997. A total of 13,717 individuals from 3344 families were included in the study. To localise quantitative trait loci (QTLs) involved in anxiety and depression, the survey data were used to select the most informative families for a genome-wide search. For each individual a genetic factor score was computed, based on a genetic multivariate analysis of anxiety, depression, neuroticism and somatic anxiety. A family was selected if at least two siblings (or DZ twins) had extreme factor scores. Both discordant (high-low) and concordant (high-high and low-low) pairs were included in the selected sample. Once an extreme sibling pair was selected, all family members (parents and additional siblings of the selected pair) who had at least once returned a questionnaire booklet were asked to provide a DNA sample. In total, 2724 individuals from 563 families (1007 parents and 1717 offspring) were approached and 1975 individuals from 479 families (643 patients and 1332 offspring) complied by returning a buccal swab for DNA isolation. All offspring from selected families were asked to participate in a psychiatric interview and in a 24-hour ambulatory assessment of cardiovascular parameters and cortisol. The interview consisted of the WHO-Composite International Diagnostic Interview and was administered to 1253 offspring. In this paper we describe the genetic-epidemiological analyses of the survey data on anxiety, somatic anxiety, neuroticism and depression. We detail how these data were used to select families for the QTL study and discuss strategies that may help elucidate the molecular pathways leading from genes to anxious depression.