Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Birth outcomes of twins after multifetal pregnancy reduction compared with primary twins.

BACKGROUND: The introduction of assisted reproductive technology and the trend of increasing maternal age at conception have contributed to a significant rise in the incidence of multiple pregnancies. Multiple pregnancies bear several inherent risks for both mother and child. These risks increase with plurality and type of chorionicity. Multifetal pregnancy reduction is the selective abortion of ≥1 fetuses to improve the outcome of the remaining fetus(es) by decreasing the risk of premature birth and other complications. OBJECTIVE: This study aimed to compare birth outcomes of trichorionic triplets reduced to twins with those of trichorionic triplets and primary dichorionic twins. The added value of this study is the comparison with an additional control group, namely primary dichorionic twins. STUDY DESIGN: This was a retrospective cohort study. Data from January 1990 to November 2016 were collected from the East Flanders Prospective Twin Survey, one of the largest European multiple birth registries. A total of 85 trichorionic triplet pregnancies (170 neonates) undergoing multifetal pregnancy reduction to twins were compared with 5093 primary dichorionic twin pregnancies (10,186 neonates) and 104 expectantly managed trichorionic triplet pregnancies (309 neonates). The assessed outcomes were gestational age at delivery, birthweight, and small for gestational age. RESULTS: Pregnancy reduction from triplets to twins was associated with higher birthweight (+365.44 g; 95% confidence interval, 222.75-508.14 g; P<.0001) and higher gestational age (1.7 weeks; 95% confidence interval, 0.93-2.46; P<.0001) compared with ongoing trichorionic triplets after adjustment for sex, parity, method of conception, birth year, and maternal age. A trend toward lower risk of small for gestational age was observed. Reduced triplets had, on average, lower birthweight (-263.12 g; 95% confidence interval, -371.80 to -154.44 g; P<.0001) and lower gestational age (-1.13 weeks; 95% confidence interval, -1.70 to -0.56; P=.0001) compared with primary twins. No statistically significant difference was observed between primary twins and reduced triplets that reached 32 weeks of gestation. CONCLUSION: Multifetal pregnancy reduction from trichorionic triplets to twins significantly improved birth outcomes. This suggests that multifetal pregnancy reduction of trichorionic triplets to twins is medically justifiable. However, the birth outcomes of primary twins before 32 weeks of gestation are still better than those of reduced triplets. The process of multifetal pregnancy reduction includes at least 1 fetal death by definition, and thus prevention of higher-order pregnancies is preferable.

Associations between childhood adversity, psychiatric symptoms, and self-esteem outcomes in adolescents and young adults: An experience sampling study.

OBJECTIVES: Self-esteem and self-esteem stability are important factors during adolescence and young adulthood that can be negatively impacted by childhood adversity and psychiatric symptoms. We examined whether childhood adversity and psychiatric symptoms are associated with decreased global self-esteem as well as increased self-esteem instability as measured with experience sampling method. In addition, we examined if childhood adversity moderates the association between psychiatric symptoms and self-esteem outcomes. METHODS: Our study consisted of 788 adolescents and young adults who were part of a twin pair. The twin structure was not of interest to the current study. Mean age was 16.8 (SD = 2.38, range: 14-25), 42% was male. We used a multilevel modeling approach to examine our hypotheses to account for the presence of twins in the data set. RESULTS: Childhood adversity and psychiatric symptoms were negatively associated with global self-esteem (respectively standardized ß = -.18, SE = 0.04, p < .0001 and standardized ß = -.45, SE = 0.04, p < .0001), with a larger effect for psychiatric symptoms. Similarly, both were associated with increased self-esteem instability (respectively standardized ß = .076, SE = 0.025, p = .002 and standardized ß = .11, SE = 0.021, p < .0001). In addition, interactions between childhood adversity and psychiatric symptoms on both global self-esteem (standardized ß = .06, SE = 0.01, p < .0001) and self-esteem instability (standardized ß = -.002, SE = 0.0006, p = .001) were found, showing that the negative association of psychiatric symptoms with self-esteem outcomes is less pronounced in young people with higher levels of childhood adversity, or formulated differently, is more pronounced in young people with little or no exposure to childhood adversity. CONCLUSION: Global self-esteem and self-esteem instability in young people are influenced by both current psychiatric symptomatology and exposure to childhood adversity. Those with more psychiatric symptoms show worse self-esteem and higher self-esteem instability, which is moderated by childhood adversity. For young people with high childhood adversity levels lower self-esteem and higher self-esteem instability are less influenced by reductions in psychiatric symptoms.

Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Gender differences in the associations between childhood adversity and psychopathology in the general population.

PURPOSE: To explore gender differences of the associations between childhood adversity (CA) subtypes and psychiatric symptoms in the general population. METHODS: Data of 791 participants were retrieved from a general population twin cohort. The Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire were used to assess overall psychopathology with nine symptom domains scores and total CA with exposure to five CA subtypes, respectively. The associations between CA and psychopathology were analyzed in men and women separately and were subsequently compared. RESULTS: Total CA was associated with total SCL-90 and all symptom domains without significant gender differences. However, the analyses of CA subtypes showed that the association between emotional abuse and total SCL-90 was stronger in women compared to men [χ2(1) = 4.10, P = 0.043]. Sexual abuse was significantly associated with total SCL-90 in women, but emotional neglect and physical neglect were associated with total SCL-90 in men. Exploratory analyses of CA subtypes and SCL-90 subdomains confirmed the pattern of gender-specific associations. In women, emotional abuse was associated with all symptom domains, and sexual abuse was associated with all except phobic anxiety and interpersonal sensitivity. In men, emotional neglect was associated with depression, and physical neglect was associated with phobic anxiety, anxiety, interpersonal sensitivity, obsessive-compulsive, paranoid ideation, and hostility subdomains. CONCLUSION: CA is a trans-syndromal risk factor regardless of gender. However, differential associations between CA subtypes and symptom manifestation might exist. Abuse might be particularly associated with psychopathology in women, whereas neglect might be associated with psychopathology in men.

Coping and sleep quality in youth: An Experience Sampling study.

INTRODUCTION: Sleep quality is closely linked with mental health. Two factors that influence sleep are coping style and locus of control, yet these have not been investigated in daily life. In this study, we examined associations between coping styles and sleep quality in daily life and the potential mediating effect of daily locus of control in a sample of youth, a group particularly vulnerable to developing psychopathology. METHODS: Three hundred and seventy-nine youths from the TwinssCan study participated in an Experience Sampling study, assessing sleep quality as well as state locus of control over the most negative event from the previous day. Participants also completed the Utrecht Coping List, which assessed engagement, disengagement, and emotion-focused coping. RESULTS: Disengagement, "passive reaction," and emotion-focused coping were associated with lower daily sleep quality. State locus of control did not mediate any effects of coping styles on quality of sleep. CONCLUSIONS: Disengagement, "passive reaction," and emotion-focused coping were associated with decreased sleep quality during several consecutive days, which may put youths at risk for developing future insomnia, and strain their mental well-being over time. Thus, there may be value in asking about coping when a young individual presents with sleep problems; however, impaired coping when sleeping poorly should also be considered.

The relationship between daily positive future thinking and past-week suicidal ideation in youth: An experience sampling study.

Reduced positive future thinking has been associated with suicidal ideation and behavior in adults, and appears to be exacerbated by negative affect. Yet, this has received little attention in youth. Prior research has also focused on longer-term future thinking, e.g., months and years, and relied on lab-based assessments. Using the experience sampling method (ESM), we investigated whether short-term future thinking in daily life was associated with suicidal ideation in youth and explored the role of affect in the future thinking-suicidal ideation relationship. A community sample of N = 722 adolescent twins and their non-twin siblings completed ESM as part of the TwinssCan study (n = 55 with, and n = 667 without, past-week suicidal ideation). Participants completed self-report questionnaires, including on past-week suicidal ideation as part of the SCL-90. Subsequently, daily future thinking was assessed each morning for six days with ESM. To investigate the relationship between daily positive future thinking and past-week suicidal ideation, we estimated a mixed-effects linear regression model with a random intercept for participant, including age and sex as covariates. The relationship between daily positive future thinking, past-week suicidal ideation, and average positive and negative affect from the previous day was investigated by estimating two separate mixed-effects linear regression models (one for negative affect, one for positive affect), with a random intercept for participant, and random slopes for average positive and negative affect. Our results showed that participants reporting higher past-week suicidal ideation also reported significantly less daily positive future thinking during the ESM period, and this association remained significant when controlling for previous-day average positive and negative affect. Higher average positive affect from the previous day was significantly associated with higher positive future thinking. Although average negative affect from the previous day was associated with lower positive future thinking, this association was not statistically significant. Our findings indicate that short-term future thinking relates to suicidal ideation among a non-clinical sample of adolescents. Future research should investigate the directionality of the future thinking-suicidal ideation relationship, in order to investigate whether impaired future thinking may be an early warning signal for escalating suicidal ideation in youth.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

General psychopathology and its social correlates in the daily lives of youth.

BACKGROUND: Adolescence is a period of both great social change, and of vulnerability to psychiatric distress. However, little is known about the associations between early psychopathology and social interactions at the fundamental level of daily life. To better understand the social correlates of subclinical psychopathology in adolescence, we assessed associations between general psychopathology and the quantity and quality of daily-life social interactions. METHODS: During a six-day experience sampling period, adolescent and young adult participants in Study 1 (n = 663) and Study 2 (n = 1027) reported the quantity and quality of their everyday social interactions. General psychopathology was assessed using the Symptom Checklist-90 and Brief Symptom Inventory-53. The relationship between psychopathology and each outcome variable was tested in separate multilevel linear and logistic regression models. RESULTS: General psychopathology was associated with social interaction quality. Associations between psychopathology and the number of social interactions were less apparent: In Study 1, participants with more psychopathology were not more alone, whereas Study 2 participants with higher levels of psychopathology were alone more. LIMITATIONS: Limitations include no separate investigation of distinct types of psychopathology, and relatively low compliance to the experience sampling in Study 2. CONCLUSIONS: Consistent associations between subclinical psychopathology and the quality of social interactions support the fundamentally social nature of early psychopathology. Moreover, negative experiences of social interactions may be more valuable markers of early psychopathology than a reduced quantity of social behaviors. Conceptualizations of daily-life social functioning, and prevention/intervention efforts would benefit from a greater consideration of the quality of everyday social experiences.

Be(com)ing social: Daily-life social interactions and parental bonding.

Parents are known to provide a lasting basis for their children's social development. Understanding parent-driven socialization is particularly relevant in adolescence, as an increasing social independence is developed. However, the relationship between key parenting styles of care and control and the microlevel expression of daily-life social interactions has been insufficiently studied. Adolescent and young adult twins and their nontwin siblings (N = 635; mean age = 16.6; age range = 14.2-21.9; 58.6% female; 79.5% in or having completed higher secondary/tertiary education; 2.8% speaking language other than Dutch at home) completed the Parental Bonding Instrument (PBI) on parental care and control. Participants also completed a 6-day experience sampling period (10 daily beeps, mean compliance = 68.0%) to assess daily-life social interactions. Higher overall parental bonding quality (of both parents) related to more positive social experiences in daily life (e.g., belonging in company), but not to more social behaviors (e.g., being with others). Factor analysis indicated a three-factor structure of the PBI, with care, denial of psychological autonomy, and encouragement of behavioral freedom. Paternal care was uniquely predictive of better social experiences. These findings demonstrate how parenting styles may be uniquely associated with how adolescents experience their social world, with a potentially important role for fathers in particular. This complements the long-held idea of socialization through parenting by bringing it into the context of daily life and implies how both conceptualizations of social functioning and interventions aimed at alleviating social dysfunction might benefit from a stronger consideration of day-to-day social experiences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Lower emotional complexity as a prospective predictor of psychopathology in adolescents from the general population.

Emotional complexity (EC) involves the ability to distinguish between distinct emotions (differentiation) and the experience of a large range of emotions (diversity). Lower EC has been related to psychopathology in cross-sectional studies. This study aimed to investigate (a) whether EC prospectively predicts psychopathology and (b) whether this effect is contingent on stressful life events. To further explore EC, we compared the effects of differentiation and diversity. Adolescents from the general population (N = 401) rated 8 negatively valenced emotions 10 times a day for 6 consecutive days. Further, they completed the Symptom Checklist-90 (baseline and 1-year follow-up) and a questionnaire on past year's life events at follow-up. Logistic regression analyses tested whether EC-reflected by emotion differentiation (intraclass correlation coefficient [ICC]) and diversity (diversity index [DI])-predicted prognosis (good: remitting or lacking symptoms vs. bad: worsening or persisting symptoms). EC predicted prognoses but only when based on the ICC (OREC.ICC = 1.42, p = .02). An ECICC 1 SD above average increased the probability of good prognosis from .67 to .74. This effect was not related to stressful life events (OREC × Life events = 1.03, p = .86) and disappeared when emotion intensity (mean level) was taken into account (OREC = 1.20, p = .20). Predicting future prognosis does not necessitate complex measures of emotional experience (ICC, DI) but rather might be achieved through simpler indices (mean). The discrepant effects of the ICC and DI on prognosis suggest that impaired emotion representation (ICC) plays a more important role in vulnerability to mental ill health than does low diversity of emotions (DI). (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (ß = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (ß = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.

Emotion regulation in response to daily negative and positive events in youth: The role of event intensity and psychopathology.

Environmental and individual contextual factors profoundly influence how people regulate their emotions. The current article addresses the role of event intensity and psychopathology (an admixture of depression, anxiety, and psychoticism) on emotion regulation in response to naturally occurring events. For six days each evening, a youth sample (aged 15-25, N = 713) recorded the intensity of the most positive and most negative event of the day and their subsequent emotion regulation. The intensity of negative events was positively associated with summed total emotion regulation effort, strategy diversity, engaging in rumination, situation modification, emotion expression, and sharing and negatively associated with reappraisal and acceptance. The intensity of positive events was positively associated with strategy diversity, savoring, emotion expression, and sharing. Higher psychopathology symptoms were only related to ruminating more about negative events. We interpret these findings as support for the role of context in the degree of effort and type of emotion regulation that young people engage in.

Serum gamma-glutamyl transferase, a marker of alcohol intake, is associated with telomere length and cardiometabolic risk in young adulthood.

Studies based on self-reported alcohol consumption and telomere length show inconsistent results. Therefore, we studied the association between gamma-glutamyl transferase (GGT), a widely used biomarker of alcohol intake, and telomere length. The possible health relevance in young adulthood was explored by investigating cardiometabolic risk factors. Mixed modelling was performed to examine GGT and alcohol consumption in association with telomere length in buccal cells of 211 adults between 18 and 30 years old of the East Flanders Prospective Twin Survey. In addition, we investigated the association between GGT and cardiometabolic risk factors; waist circumference, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides. Although we did not observe an association between self-reported alcohol consumption and telomere length, our results show that a doubling in serum GGT is associated with 7.80% (95% CI - 13.9 to - 1.2%; p = 0.02) shorter buccal telomeres, independently from sex, chronological age, educational level, zygosity and chorionicity, waist-to-hip ratio and smoking. The association between GGT was significant for all five cardiometabolic risk factors, while adjusting for age. We show that GGT, a widely used biomarker of alcohol consumption, is associated with telomere length and with risk factors of cardiometabolic syndrome, despite the young age of this study population.

Overnight affective dynamics and sleep characteristics as predictors of depression and its development in women.

STUDY OBJECTIVES: We examined (1) differences in overnight affective inertia (carry-over of evening affect to the next morning) for positive (PA) and negative affect (NA) between individuals with past, current, and no depression; (2) how sleep duration and quality influence overnight affective inertia in these groups, and (3) whether overnight affective inertia predicts depression development. METHODS: We used data of 579 women from the East-Flanders Prospective Twin Survey. For aim 1 and 2, individuals with past (n = 82), current (n = 26), and without (lifetime) depression (n = 471) at baseline were examined. For aim 3, we examined individuals who did (n = 58) and did not (n = 319) develop a depressive episode at 12-month follow-up. Momentary PA and NA were assessed 10 times a day for 5 days. Sleep was assessed daily with sleep diaries. Affective inertia was operationalized as the influence of evening affect on morning affect. Linear mixed-effect models were used to test the hypotheses. RESULTS: Overnight affective inertia for NA was significantly larger in the current compared to the non-depressed group, and daytime NA inertia was larger in the past compared to the non-depressed group. Overnight NA inertia was differently associated with shorter sleep duration in both depression groups and with lower sleep quality in the current compared to the non-depressed group. Overnight affective inertia did not predict depression development at 12-month follow-up. CONCLUSIONS: Current findings demonstrate the importance of studying complex affect dynamics such as overnight affective inertia in relation to depression and sleep characteristics. Replication of these findings, preferably with longer time-series, is needed.

Network dynamics of momentary affect states and future course of psychopathology in adolescents.

BACKGROUND: Recent theories argue that an interplay between (i.e., network of) experiences, thoughts and affect in daily life may underlie the development of psychopathology. OBJECTIVE: To prospectively examine whether network dynamics of everyday affect states are associated with a future course of psychopathology in adolescents at an increased risk of mental disorders. METHODS: 159 adolescents from the East-Flanders Prospective Twin Study cohort participated in the study. At baseline, their momentary affect states were assessed using the Experience Sampling Method (ESM). The course of psychopathology was operationalized as the change in the Symptom Checklist-90 sum score after 1 year. Two groups were defined: one with a stable level (n = 81) and one with an increasing level (n = 78) of SCL-symptom severity. Group-level network dynamics of momentary positive and negative affect states were compared between groups. RESULTS: The group with increasing symptoms showed a stronger connections between negative affect states and their higher influence on positive states, as well as higher proneness to form 'vicious cycles', compared to the stable group. Based on permutation tests, these differences were not statistically significant. CONCLUSION: Although not statistically significant, some qualitative differences were observed between the networks of the two groups. More studies are needed to determine the value of momentary affect networks for predicting the course of psychopathology.

Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.

BACKGROUND: Telomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood. METHODS: Telomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n = 273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n = 164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards. FINDINGS: In children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r = 0.71, P < 0.0001;) and placenta (r = 0.60, P < 0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r = 0.46, P < 0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation. INTERPRETATION: The high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life. FUNDING: European Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).

Early warning signals in psychopathology: what do they tell?

BACKGROUND: Despite the increasing understanding of factors that might underlie psychiatric disorders, prospectively detecting shifts from a healthy towards a symptomatic state has remained unattainable. A complex systems perspective on psychopathology implies that such symptom shifts may be foreseen by generic indicators of instability, or early warning signals (EWS). EWS include, for instance, increasing variability, covariance, and autocorrelation in momentary affective states-of which the latter was studied. The present study investigated if EWS predict (i) future worsening of symptoms as well as (ii) the type of symptoms that will develop, meaning that the association between EWS and future symptom shifts would be most pronounced for congruent affective states and psychopathological domains (e.g., feeling down and depression). METHODS: A registered general population cohort of adolescents (mean age 18 years, 36% male) provided ten daily ratings of their affective states for 6 consecutive days. The resulting time series were used to compute EWS in feeling down, listless, anxious, not relaxed, insecure, suspicious, and unwell. At baseline and 1-year follow-up, symptom severity was assessed by the Symptom Checklist-90 (SCL-90). We selected four subsamples of participants who reported an increase in one of the following SCL-90 domains: depression (N = 180), anxiety (N = 192), interpersonal sensitivity (N = 184), or somatic complaints (N = 166). RESULTS: Multilevel models showed that EWS in feeling suspicious anticipated increases in interpersonal sensitivity, as hypothesized. EWS were absent for other domains. While the association between EWS and symptom increases was restricted to the interpersonal sensitivity domain, post hoc analyses showed that symptom severity at baseline was related to heightened autocorrelations in congruent affective states for interpersonal sensitivity, depression, and anxiety. This pattern replicated in a second, independent dataset. CONCLUSIONS: The presence of EWS prior to symptom shifts may depend on the dynamics of the psychopathological domain under consideration: for depression, EWS may manifest only several weeks prior to a shift, while for interpersonal sensitivity, EWS may already occur 1 year in advance. Intensive longitudinal designs where EWS and symptoms are assessed in real-time are required in order to determine at what timescale and for what type of domain EWS are most informative of future psychopathology.

Residential green space and child intelligence and behavior across urban, suburban, and rural areas in Belgium: A longitudinal birth cohort study of twins.

BACKGROUND: Exposure to green space has beneficial effects on several cognitive and behavioral aspects. However, to our knowledge, no study addressed intelligence as outcome. We investigated whether the level of urbanicity can modify the association of residential green space with intelligence and behavior in children. METHODS AND FINDINGS: This study includes 620 children and is part of the East Flanders Prospective Twin Survey (EFPTS), a registry of multiple births in the province of East Flanders, Belgium. Intelligence was assessed with the Wechsler Intelligence Scale for Children-Revised (WISC-R) in 620 children (310 twin pairs) between 7 and 15 years old. From a subset of 442 children, behavior was determined based on the Achenbach Child Behavior Checklist (CBCL). Prenatal and childhood residential addresses were geocoded and used to assign green space indicators. Mixed modeling was performed to investigate green space in association with intelligence and behavior while adjusting for potential confounding factors including sex, age, parental education, neighborhood household income, year of assessment, and zygosity and chorionicity. We found that residential green space in association with both intelligence and behavior in children was modified by the degree of urbanicity (p < 0.001). In children living in an urban environment, multivariable adjusted mixed modeling analysis revealed that an IQR increment of residential green space (3,000-m radius) was associated with a 2.6 points (95% CI 1.4-3.9; p < 0.001) higher total intelligence quotient (IQ) and 2.0 points (95% CI -3.5 to -0.4; p = 0.017) lower externalizing behavioral score. In children residing in a rural or suburban environment, no association was found. A limitation of this study is that no information was available on school location and the potential for unmeasured confounding (e.g., time spend outdoors). CONCLUSIONS: Our results indicate that residential green space may be beneficial for the intellectual and the behavioral development of children living in urban areas. These findings are relevant for policy makers and urban planners to create an optimal environment for children to develop their full potential.

Genetic and environmental variation in educational attainment: an individual-based analysis of 28 twin cohorts.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a2 = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a2 = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29-0.33 and c2 = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.