The stability and change of wellbeing across the lifespan: a longitudinal twin-sibling study.

BACKGROUND: Wellbeing is relatively stable over the life span. However, individuals differ in this stability and change. One explanation for these differences could be the influence of different genetic or environmental factors on wellbeing over time. METHODS: To investigate causes of stability and change of wellbeing across the lifespan, we used cohort-sequential data on wellbeing from twins and their siblings of the Netherlands Twin Register (NTR) (total N = 46.885, 56% females). We organized wellbeing data in multiple age groups, from childhood (age 5), to adolescence, up to old age (age 61+). Applying a longitudinal genetic simplex model, we investigated the phenotypic stability of wellbeing and continuity and change in genetic and environmental influences. RESULTS: Wellbeing peaked in childhood, decreased during adolescence, and stabilized during adulthood. In childhood and adolescence, around 40% of the individual differences was explained by genetic effects. The heritability decreased toward old adulthood (35-24%) and the contribution of unique environmental effects increased to 76%. Environmental innovation was found at every age, whereas genetic innovation was only observed during adolescence (10-18 years). In childhood and adulthood, the absence of genetic innovation indicates a stable underlying set of genes influencing wellbeing during these life phases. CONCLUSION: These findings provide insights into the stability and change of wellbeing and the genetic and environmental influences across the lifespan. Genetic effects were mostly stable, except in adolescence, whereas the environmental innovation at every age suggests that changing environmental factors are a source of changes in individual differences in wellbeing over time.

Disentangling potential causal effects of educational duration on well-being, and mental and physical health outcomes.

BACKGROUND: Extensive research has focused on the potential benefits of education on various mental and physical health outcomes. However, whether the associations reflect a causal effect is harder to establish. METHODS: To examine associations between educational duration and specific aspects of well-being, anxiety and mood disorders, and cardiovascular health in a sample of European Ancestry UK Biobank participants born in England and Wales, we apply four different causal inference methods (a natural policy experiment leveraging the minimum school-leaving age, a sibling-control design, Mendelian randomization [MR], and within-family MR), and assess if the methods converge on the same conclusion. RESULTS: A comparison of results across the four methods reveals that associations between educational duration and these outcomes appears predominantly to be the result of confounding or bias rather than a true causal effect of education on well-being and health outcomes. Although we do consistently find no associations between educational duration and happiness, family satisfaction, work satisfaction, meaning in life, anxiety, and bipolar disorder, we do not find consistent significant associations across all methods for the other phenotypes (health satisfaction, depression, financial satisfaction, friendship satisfaction, neuroticism, and cardiovascular outcomes). CONCLUSIONS: We discuss inconsistencies in results across methods considering their respective limitations and biases, and additionally discuss the generalizability of our findings in light of the sample and phenotype limitations. Overall, this study strengthens the idea that triangulation across different methods is necessary to enhance our understanding of the causal consequences of educational duration.

Genetic confounding in the association of early motor development with childhood and adolescent exercise behavior.

INTRODUCTION: Early motor development has been found to be a predictor of exercise behavior in children and adolescents, but whether this reflects a causal effect or confounding by genetic or shared environmental factors remains to be established. METHODS: For 20,911 complete twin pairs from the Netherlands Twin Register a motor development score was obtained from maternal reports on the timing of five motor milestones. During a 12-year follow-up, subsamples of the mothers reported on the twins' ability to perform seven gross motor skills ability (N = 17,189 pairs), and weekly minutes of total metabolic equivalents of task (MET) spent on sports and exercise activities at age 7 (N = 3632 pairs), age 10 (N = 3735 pairs), age 12 (N = 7043 pairs), and age 14 (N = 3990 pairs). Multivariate phenotypic and genetic regression analyses were used to establish the predictive strength of the two motor development traits for future exercise behavior, the contribution of genetic and shared environmental factors to the variance in all traits, and the contribution of familial confounding to the phenotypic prediction. RESULTS: Significant heritability (h2) and shared environmental (c2) effects were found for early motor development in boys and girls (h2 = 43-65%; c2 = 16-48%). For exercise behavior, genetic influences increased with age (boys: h2age7 = 22% to h2age14 = 51%; girls: h2age7 = 3% to h2age14 = 18%) paired to a parallel decrease in the influence of the shared environment (boys: c2age7 = 68% to c2age14 = 19%; girls: c2age7 = 80% to c2age14 = 48%). Early motor development explained 4.3% (p < 0.001) of the variance in future exercise behavior in boys but only 1.9% (p < 0.001) in girls. If the effect in boys was due to a causal effect of motor development on exercise behavior, all of the factors influencing motor development would, through the causal chain, also influence future exercise behavior. Instead, only the genetic parts of the regression of exercise behavior on motor development were significant. Shared and unique environmental parts of the regression were largely non-significant, which is at odds with the causal hypothesis. CONCLUSION: No support was found for a direct causal effect in the association between rapid early motor development on future exercise behavior. In boys, early motor development appears to be an expression of the same genetic factors that underlie the heritability of childhood and early adolescent exercise behavior.

Distinguishing happiness and meaning in life from depressive symptoms: A GWAS-by-subtraction study in the UK Biobank.

Hedonic (happiness) and eudaimonic (meaning in life) well-being are negatively related to depressive symptoms. Genetic variants play a role in this association, reflected in substantial genetic correlations. We investigated the overlap and differences between well-being and depressive symptoms, using results of Genome-Wide Association studies (GWAS) in UK Biobank. Subtracting GWAS summary statistics of depressive symptoms from those of happiness and meaning in life, we obtained GWASs of respectively "pure" happiness (neffective = 216,497) and "pure" meaning (neffective = 102,300). For both, we identified one genome-wide significant SNP (rs1078141 and rs79520962, respectively). After subtraction, SNP heritability reduced from 6.3% to 3.3% for pure happiness and from 6.2% to 4.2% for pure meaning. The genetic correlation between the well-being measures reduced from 0.78 to 0.65. Pure happiness and pure meaning became genetically unrelated to traits strongly associated with depressive symptoms, including loneliness, and psychiatric disorders. For other traits, including ADHD, educational attainment, and smoking, the genetic correlations of well-being versus pure well-being changed substantially. GWAS-by-subtraction allowed us to investigate the genetic variance of well-being unrelated to depressive symptoms. Genetic correlations with different traits led to new insights about this unique part of well-being. Our results can be used as a starting point to test causal relationships with other variables, and design future well-being interventions.

Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder.

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.

Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

Bias in Gene-by-Environment Interaction Effects with Sum Scores; An Application to Well-being Phenotypes.

In the current study, we investigated the influence of using skewed sum scores on estimated gene-by-environment interaction effects (GxE) for life satisfaction and happiness with perceived social support. To this end, we analyzed item-level data from a large adult twin sample (Ns between 3610 and 11,305) of the Netherlands Twin Register. Item response theory (IRT) models were incorporated in unmeasured (univariate) GxE models, and measured GxE models (with social support as moderator). We found that skewness introduced spurious GxE effects, with the largest effect for the most skewed variable (social support). Finally, in the IRT model for life satisfaction, but not for happiness, heritability estimates decreased with higher social support, while this was not observed when analyzing sum scores. Together, our results indicate that IRT can be used to address psychometric issues related to the use of sum scores, especially in the context of GxE, for complex traits like well-being.

Integrative Multi-omics Analysis of Childhood Aggressive Behavior.

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia.

Both common and rare genetic variants (minor allele frequency >1% and <0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene-sets. Four types of gene-sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene-sets. We show that common as well as ultra-rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

Internalizing problems before and during the COVID-19 pandemic in independent samples of Dutch children and adolescents with and without pre-existing mental health problems.

The aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19 pandemic, consisting of two Dutch general population samples (GS) and two clinical samples (CS) referred to youth/psychiatric care. Measures of internalizing problems were obtained from ongoing data collections pre-pandemic (NGS = 35,357; NCS = 4487) and twice during the pandemic, in Apr-May 2020 (NGS = 3938; clinical: NCS = 1008) and in Nov-Dec 2020 (NGS = 1489; NCS = 1536), in children and adolescents (8-18 years) with parent (Brief Problem Monitor) and/or child reports (Patient-Reported Outcomes Measurement Information System®). Results show that, in the general population, internalizing problems were higher during the first peak of the pandemic compared to pre-pandemic based on both child and parent reports. Yet, over the course of the pandemic, on both child and parent reports, similar or lower levels of internalizing problems were observed. Children in the clinical population reported more internalizing symptoms over the course of the pandemic while parents did not report differences in internalizing symptoms from pre-pandemic to the first peak of the pandemic nor over the course of the pandemic. Overall, the findings indicate that children and adolescents of both the general and clinical population were affected negatively by the pandemic in terms of their internalizing problems. Attention is therefore warranted to investigate long-term effects and to monitor if internalizing problems return to pre-pandemic levels or if they remain elevated post-pandemic.

Daily affect intensity and variability of adolescents and their parents before and during a COVID-19 lockdown.

INTRODUCTION: The corona virus (COVID-19) pandemic may have a prolonged impact on people's lives, with multiple waves of infections and lockdowns, but how a lockdown may alter emotional functioning is still hardly understood. METHODS: In this 100-daily diaries study, we examined how to affect intensity and variability of adolescents (N = 159, Mage = 13.3, 61.6% female) and parents (N = 159, Mage = 45.3, 79.9% female) changed after the onset and during (>50 days) the second COVID-19 lockdown in the Netherlands, using preregistered piecewise growth models. RESULTS: We found only an unexpected increase in parents' positive affect intensity after the lockdown onset, but no immediate changes in negative affect intensity or variability. However, both adolescents and parents reported gradual increases in negative affect intensity and variability as the lockdown prolonged. Lockdown effects did not differ between adolescents and parents. However, within groups, individuals differed. The individual differences in the effects were partly explained by life satisfaction, depressive symptoms, and self-reported lockdown impact. CONCLUSIONS: Overall, these findings suggests that a lockdown triggers changes in daily affective well-being especially as the lockdown prolongs. Individual differences in the effects indicate heterogeneity in the impact of the lockdown on daily affect that was partly explained by baseline life satisfaction and depressive symptoms. However, more knowledge on the causes of this heterogeneity is needed to be able to increase resilience to lockdown effects in the population.

Multivariate analyses of molecular genetic associations between childhood psychopathology and adult mood disorders and related traits.

Ubiquitous associations have been detected between different types of childhood psychopathology and polygenic risk scores based on adult psychiatric disorders and related adult outcomes, indicating that genetic factors partly explain the association between childhood psychopathology and adult outcomes. However, these analyses in general do not take into account the correlations between the adult trait and disorder polygenic risk scores. This study aimed to further clarify the influence of genetic factors on associations between childhood psychopathology and adult outcomes by accounting for these correlations. Using a multivariate multivariable regression, we analyzed associations of childhood attention-deficit/hyperactivity disorder (ADHD), internalizing, and social problems, with polygenic scores (PGS) of adult disorders and traits including major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI), derived for 20,539 children aged 8.5-10.5 years. After correcting for correlations between the adult phenotypes, major depression PGS were associated with all three childhood traits, that is, ADHD, internalizing, and social problems. In addition, BMI PGS were associated with ADHD symptoms and social problems, while neuroticism PGS were only associated with internalizing problems and educational attainment PGS were only associated with ADHD symptoms. PGS of bipolar disorder, subjective well-being, and insomnia were not associated with any childhood traits. Our findings suggest that associations between childhood psychopathology and adult traits like insomnia and subjective well-being may be primarily driven by genetic factors that influence adult major depression. Additionally, specific childhood phenotypes are genetically associated with educational attainment, BMI and neuroticism.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Gene-by-Crisis Interaction for Optimism and Meaning in Life: The Effects of the COVID-19 Pandemic.

The corona virus disease 2019 (COVID-19) pandemic and the restrictions to reduce the spread of the virus has had a large impact on daily life. We investigated the individual differences in the effect of the COVID-19 pandemic and first lockdown on optimism and meaning in life in a sample from the Netherlands Twin Register. Participants completed surveys before (N = 9964, Mean age: 48.2, SD = 14.4) and during the first months of the pandemic (i.e. April-May 2020, N = 17,464, Mean age: 44.6 SD = 14.8), with a subsample completing both surveys (N = 6461, Mean age T1: 48.8, SD = 14.5). We applied genetic covariance structure models to twin data to investigate changes in the genetic architecture of the outcome traits due to the pandemic and the interaction of genes with the environmental exposure. Although 56% and 35% of the sample was negatively affected by the pandemic in their optimism and meaning in life, many participants were stable (32% and 43%) or even showed increased optimism and meaning in life (11% and 22%). Subgroups, specifically women, higher educated people, and people with poorer health, experienced larger negative effects. During the first months of the pandemic, slightly lower heritability estimates for optimism and meaning in life (respectively 20% and 25%) were obtained compared to pre-pandemic (respectively 26% and 32%), although confidence intervals overlap. The lower than unity genetic correlations across time (.75 and .63) suggest gene-environment interactions, where the expression of genes that influence optimism and meaning in life differs before and during the pandemic. The COVID-19 pandemic is a strong exposure that leads to imbalanced effects on the well-being of individuals. Some people decrease in well-being, while others get more optimistic and consider their lives as more meaningful during the pandemic. These differences are partly explained by individual differences in genetic sensitivity to extreme environmental change. More knowledge on the person-specific response to specific environmental variables underlying these individual differences is urgently needed to prevent further inequality.

Genetic Risk for Smoking: Disentangling Interplay Between Genes and Socioeconomic Status.

This study aims to disentangle the contribution of genetic liability, educational attainment (EA), and their overlap and interaction in lifetime smoking. We conducted genome-wide association studies (GWASs) in UK Biobank (N = 394,718) to (i) capture variants for lifetime smoking, (ii) variants for EA, and (iii) variants that contribute to lifetime smoking independently from EA ('smoking-without-EA'). Based on the GWASs, three polygenic scores (PGSs) were created for individuals from the Netherlands Twin Register (NTR, N = 17,805) and the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2, N = 3090). We tested gene-environment (G × E) interactions between each PGS, neighborhood socioeconomic status (SES) and EA on lifetime smoking. To assess if the PGS effects were specific to smoking or had broader implications, we repeated the analyses with measures of mental health. After subtracting EA effects from the smoking GWAS, the SNP-based heritability decreased from 9.2 to 7.2%. The genetic correlation between smoking and SES characteristics was reduced, whereas overlap with smoking traits was less affected by subtracting EA. The PGSs for smoking, EA, and smoking-without-EA all predicted smoking. For mental health, only the PGS for EA was a reliable predictor. There were suggestions for G × E for some relationships, but there were no clear patterns per PGS type. This study showed that the genetic architecture of smoking has an EA component in addition to other, possibly more direct components. PGSs based on EA and smoking-without-EA had distinct predictive profiles. This study shows how disentangling different models of genetic liability and interplay can contribute to our understanding of the etiology of smoking.

Persistence of parental-reported asthma at early ages: A longitudinal twin study.

BACKGROUND: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. METHODS: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. RESULTS: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. CONCLUSION: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7.

Genetic factors explain a significant part of associations between adolescent well-being and the social environment.

Socio-environmental factors play an important role in adolescent well-being, but potential genetic contributions to these associations are rarely assessed. To address this gap in the literature, associations between well-being and family conflict and functioning, number of friends, friendship importance and satisfaction, and leisure time variables were studied in N = ~ 4700 twin pairs from the Netherlands Twin Register, us ing generalized estimating equations and twin-difference scores. When twin-difference scores indicated a role for genetic factors, we used bivariate genetic models to quantify genetic and environmental contributions to these associations. We identify significant associations between well-being and family functioning, family conflict, different leisure time activities, number of friends, and satisfaction with friendships. Additionally, we find evidence for large (73-91%) genetic influence on the associations between well-being and family conflict and functioning, leisure time sport/scouting clubs, and satisfaction with friendships. Finally, findings support the hypothesis of a causal association between well-being and family conflict and functioning. These findings have important implications for research into the social correlates of well-being in adolescence, as not taking genetic factors into account leads to overestimations of the influence of identified correlates and consequently to recommendations of these correlates as intervention targets.

Overview of CAPICE-Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie Sklodowska-Curie International Training Network.

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

A Re-evaluation of Candidate Gene Studies for Well-Being in Light of Genome-Wide Evidence.

Ever since twin-family studies found that a substantial amount (± 40%) of the variation in well-being can be explained by genetic variation, several candidate genes have been proposed explaining this variation. However, these candidate gene and candidate gene-by-environment interaction studies have been surrounded by controversy regarding the validity and replication of their results. In the present study, we review the existing candidate gene literature for well-being. First, we perform a systematic literature search that results in the inclusion of 41 studies. After describing the results of the included studies, we evaluated the included candidate polymorphisms by (1) looking up the results for the studied candidate SNPs in a large well-being genome-wide association study, (2) performing association analyses in UK biobank (UKB) data for the candidate variable number tandem repeats (VNTR) and the APOE ε4 allele, and (3) studying possible candidate interactions with positive and negative environmental moderators using UKB data. We find no support for any of the candidate genes or candidate gene-environment interactions for well-being, with the exception of two SNPs that were chosen based on genome-wide evidence. While the generalizability of our findings is limited by our phenotype and environment definitions, we strongly advise well-being researchers to abandon the candidate gene approach in the field of well-being and move toward genome-wide approaches. Supplementary Information: The online version contains supplementary material available at 10.1007/s10902-022-00538-x.

Genetic Influences on the Covariance and Genetic Correlations in a Bivariate Twin Model: An Application to Well-Being.

The distinction between genetic influences on the covariance (or bivariate heritability) and genetic correlations in bivariate twin models is often not well-understood or only one is reported while the results show distinctive information about the relation between traits. We applied bivariate twin models in a large sample of adolescent twins, to disentangle the association between well-being (WB) and four complex traits (optimism, anxious-depressed symptoms (AD), aggressive behaviour (AGG), and educational achievement (EA)). Optimism and AD showed respectively a strong positive and negative phenotypic correlation with WB, the negative correlation of WB and AGG is lower and the correlation with EA is nearly zero. All four traits showed a large genetic contribution to the covariance with well-being. The genetic correlations of well-being with optimism and AD are strong and smaller for AGG and EA. We used the results of the models to explain what information is retrieved based on the bivariate heritability versus the genetic correlations and the (clinical) implications.