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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.
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Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Humanos , Causalidade , Escolaridade , Fenótipo , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Traditional epidemiological evidence suggests various associations exist between alcohol and mental/cognitive health outcomes. However, whether these reflect causal relationships remains unclear. Mendelian randomization (MR) - a kind of instrumental variable analysis using genetic variants to proxy for an exposure of interest - has the potential to improve causal inference from observational data. SUMMARY: In the first part of this review, the challenges of causal inference in the field are discussed, and a theoretical and practical introduction to the technique of MR is given. Next, we report on literature searches performed to update a previous systematic review of MR studies evaluating alcohol-mental health relationships. Twelve relevant studies were identified and considered in the context of the 22 studies included in the previous review. While the reviewed MR literature suggests possible causal relationships/a lack thereof, for the most part, the nature of causal relationships between alcohol and mental health remains unclear. KEY MESSAGES: MR is beginning to yield valuable insights into the causal effects of (problematic) alcohol consumption on mental and cognitive health outcomes. Future studies must be mindful of the technique's underlying assumptions and should allow for potential nonlinearity in relationships. Triangulating across sensitivity methods within MR studies, as well as between MR studies and other methods for enhanced causal inference, will be crucial.
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Consumo de Bebidas Alcoólicas , Análise da Randomização Mendeliana , Saúde Mental , Humanos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , CausalidadeRESUMO
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.
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Estudo de Associação Genômica Ampla , Gravidez de Gêmeos , Adulto , Peso ao Nascer/genética , Desenvolvimento Fetal , Idade Gestacional , Humanos , Recém-Nascido , Gêmeos/genéticaRESUMO
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.
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COVID-19 , Interação Gene-Ambiente , Pandemias , Adulto , Controle de Doenças Transmissíveis , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Otimismo , Sistema de Registros , GêmeosRESUMO
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.
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Saúde do Adolescente , Amigos , Adolescente , Humanos , Países Baixos , Satisfação Pessoal , Meio Social , Gêmeos/genéticaRESUMO
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.
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The adult self report (ASR) is a well-validated instrument with multiple scales relating to adult psychopathology. Recently, an 18-item version has been introduced, the brief problem monitor (BPM) to measure Internalizing behavior (INT), Externalizing behavior (EXT), and attention problems (ATT). The present study compared the BPM and ASR and investigated how well the BPM can serve as a supplement or an alternative for the ASR for specific clinical and scientific purposes. In a large sample of adult twins (N = 9.835) from the Netherlands Twin Register (NTR), we compared the internal consistency, clinical classification concordance, means, and variances of the ASR and BPM. Using the classical twin design, we investigated the genetic covariance structure. For external validation, the associations between subjective well-being and different subscales of the ASR and BPM were compared. The internal consistency of the BPM scales (around α = 0.75) was somewhat lower than the ASR (α ~ 0.85). The BPM Externalizing scale showed the lowest internal consistency (α = 0.63). ASR and BPM scores showed good clinical classification concordance (0.61-0.80) and high correlations (r > 0.88). A small reversed sex difference in the BPM Externalizing scale appeared (women > men). Genetic (0.34-0.54) and environmental components (0.46-0.66) explained the variance to a similar extent for the ASR and BPM. The phenotypic and genetic associations with well-being were comparable. In situations where sum scores are sufficient, the BPM performs as well as the longer ASR. Depending on the situation and goal, it is worth considering the BPM as an alternative for the ASR to reduce the participant burden.
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Monitorização Fisiológica , Autorrelato , Adolescente , Adulto , Feminino , Humanos , Masculino , Inquéritos e Questionários , Gêmeos/genéticaRESUMO
Mendelian randomization (MR) uses genetic variants associated with an exposure (eg, high blood pressure) as instrumental variables to test causal effects on an outcome (eg, atrial fibrillation [AF]). By leveraging the random assortment of genetic variants during gamete formation, MR reduces biases like confounding and reverse causation. We screened 391 papers, examining 277 that applied MR to investigate arrhythmia and, in others, cardiovascular traits, lifestyle, behavioral traits, and body composition. Our analysis focused on MR studies of arrhythmia and cardiovascular traits. Key findings highlight high systolic blood pressure, low resting heart rate, elevated cardiac troponin I levels, coronary artery disease, and heart failure as risk factors for AF, whereas AF itself increases heart failure risk. As genetic data become more accessible, MR's relevance grows. Sensitivity analyses and integrating MR with other methodologies in a triangulation framework enhance the robustness of causal inferences by navigating different biases.
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Tobacco use and major depression are both leading contributors to the global burden of disease and are also highly comorbid. Previous research indicates bi-directional causality between tobacco use and depression, but the mechanisms that underlie this causality are unclear, especially for the causality from tobacco use to depression. Here we narratively review the available evidence for a potential causal role of gray matter volume in the association. We summarize the findings of large existing neuroimaging meta-analyses, studies in UK Biobank, and the Enhancing NeuroImaging Genetics through MetaAnalysis (ENIGMA) consortium and assess the overlap in implicated brain areas. In addition, we review two types of methods that allow us more insight into the causal nature of associations between brain volume and depression/smoking: longitudinal studies and Mendelian Randomization studies. While the available evidence suggests overlap in the alterations in brain volumes implicated in tobacco use and depression, there is a lack of research examining the underlying pathophysiology. We conclude with recommendations on (genetically-informed) causal inference methods useful for studying these associations.
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Depressão , Substância Cinzenta , Fumar , Humanos , Depressão/diagnóstico por imagem , Estudo de Associação Genômica Ampla , Substância Cinzenta/diagnóstico por imagem , Fumar/efeitos adversosRESUMO
Findings from behavioral and genetic studies indicate a potential role for the involvement of brain structures and brain functioning in well-being. We performed a systematic review on the association between brain structures or brain functioning and well-being, including 56 studies. The 11 electroencephalography (EEG) studies suggest a larger alpha asymmetry (more left than right brain activation) to be related to higher well-being. The 18 Magnetic Resonance Imaging (MRI) studies, 26 resting-state functional MRI studies and two functional near-infrared spectroscopy (fNIRS) studies identified a wide range of brain regions involved in well-being, but replication across studies was scarce, both in direction and strength of the associations. The inconsistency could result from small sample sizes of most studies and a possible wide-spread network of brain regions with small effects involved in well-being. Future directions include well-powered brain-wide association studies and innovative methods to more reliably measure brain activity in daily life.
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Mapeamento Encefálico , Eletroencefalografia , Humanos , Mapeamento Encefálico/métodos , Eletroencefalografia/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Córtex Cerebral , Imageamento por Ressonância MagnéticaRESUMO
To understand the pathways through which well-being contributes to health, we performed a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines on the association between well-being and physiological markers in four categories, neurotransmitters, hormones, inflammatory markers, and microbiome. We identified 91 studies. Neurotransmitter studies (knumber of studies=9) reported only a possible positive association between serotonin and well-being. For the hormone studies (k = 48), a lower momentary cortisol level was related to higher well-being (meta-analytic r = -0.06), and a steeper diurnal slope of cortisol levels. Inflammatory marker studies (k = 36) reported negative or non-significant relations with well-being, with meta-analytic estimates of respectively r = -0.07 and r = -0.05 for C-reactive protein and interleukin-6. Microbiome studies (k = 4) reported inconsistent associations between different bacteria abundance and well-being. The results indicate possible but small roles of serotonin, cortisol, and inflammatory markers in explaining differences in well-being. The inconsistent and limited results for other markers and microbiome require further research. Future directions for a complete picture of the physiological factors underlying well-being are proposed.
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Hidrocortisona , Microbiota , Biomarcadores , Humanos , Hidrocortisona/metabolismo , Neurotransmissores , SerotoninaRESUMO
BACKGROUND: Identifying modifiable factors associated with well-being is of increased interest for public policy guidance. Developments in record linkage make it possible to identify what contributes to well-being from a myriad of factors. To this end, we link two large-scale data resources; the Geoscience and Health Cohort Consortium, a collection of geo-data, and the Netherlands Twin Register, which holds population-based well-being data. OBJECTIVE: We perform an Environment-Wide Association Study (EnWAS), where we examine 139 neighbourhood-level environmental exposures in relation to well-being. METHODS: First, we performed a generalized estimation equation regression (N = 11,975) to test for the effects of environmental exposures on well-being. Second, to account for multicollinearity amongst exposures, we performed principal component regression. Finally, using a genetically informative design, we examined whether environmental exposure is driven by genetic predisposition for well-being. RESULTS: We identified 21 environmental factors that were associated with well-being in the domains: housing stock, income, core neighbourhood characteristics, livability, and socioeconomic status. Of these associations, socioeconomic status and safety are indicated as the most important factors to explain differences in well-being. No evidence of gene-environment correlation was found. SIGNIFICANCE: These observed associations, especially neighbourhood safety, could be informative for policy makers and provide public policy guidance to improve well-being. Our results show that linking databases is a fruitful exercise to identify determinants of mental health that would remain unknown by a more unilateral approach.
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Saúde Mental , Características de Residência , Estudos de Coortes , Exercício Físico , Humanos , Classe Social , Fatores SocioeconômicosRESUMO
By treating the coronavirus disease 2019 (COVID-19) pandemic as a natural experiment, we examine the influence of substantial environmental change (i.e., lockdown measures) on individual differences in quality of life (QoL) in the Netherlands. We compare QoL scores before the pandemic (N = 25,772) to QoL scores during the pandemic (N = 17,222) in a sample of twins and their family members. On a 10-point scale, we find a significant decrease in mean QoL from 7.73 (SD = 1.06) before the pandemic to 7.02 (SD = 1.36) during the pandemic (Cohen's d = 0.49). Additionally, variance decomposition shows an increase in unique environmental variance during the pandemic (0.30-1.08), and a decrease in the heritability estimate from 30.9% to 15.5%. We hypothesize that the increased environmental variance is the result of lockdown measures not impacting everybody equally. Whether these effects persist over longer periods and how they impact health inequalities remain topics for future investigation.
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COVID-19 , Pandemias , Humanos , Qualidade de Vida , Controle de Doenças Transmissíveis , FamíliaRESUMO
RATIONALE: The coronavirus disease 2019 (COVID-19) pandemic and consequent lockdown measures have had a large impact on people's lives. Recent evidence suggests that self-rated health (SRH) scores remained relatively stable or increased during the pandemic. OBJECTIVE: For the current project, we examine potential changes in the variance decomposition of SRH before and during the COVID-19 pandemic in the Netherlands. METHODS: We analyse data from the Netherlands Twin Register to examine pre-pandemic SRH scores (N = 16,127), pandemic SRH scores (N = 17,451), and SRH difference scores (N = 7464). Additionally, we perform bivariate genetic analyses to estimate genetic and environmental variance components in pre-pandemic and pandemic SRH, and estimate the genetic correlation to assess potential gene-environment interaction. RESULTS: The majority of the sample (66.7%) reported the same SRH before and during the pandemic, while 10.8% reported a decrease, and 22.5% an increase. Individuals who reported good/excellent SRH before the pandemic were most likely to report unchanged SRH during the pandemic, and individuals with bad/mediocre/reasonable SRH more often reported increased SRH. The bivariate longitudinal genetic model reveals no significant change in variance decomposition of SRH from before to during the pandemic, with a heritability estimate of 45% (CI 36%-52%). We found that the genetic correlation could be constrained to 1, and a moderate unique environmental correlation (rE = 0.49, CI = 0.37 to 0.60). CONCLUSIONS: We theorize that the increases in SRH are explained by uninfected individuals evaluating their health more positively than under normal circumstances (partly through social comparison with infected individuals), rather than actual improvements. As the same genes are expressed under different environmental exposures, these results imply no evidence for gene-environment interaction. While different environmental factors might influence SRH at the two time-points, the influence of environmental factors does not become relatively more important during the pandemic.
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COVID-19 , Saúde da População , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Nível de Saúde , Humanos , Estudos Longitudinais , PandemiasRESUMO
The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.
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Bancos de Espécimes Biológicos , Proteínas Correpressoras/genética , Prole de Múltiplos Nascimentos/genética , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.