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Background and Aims: Studies on adolescent alcohol use and cognition are often unable to separate the potential causal effects of alcohol use on cognition from shared etiological influences, including genetic influences or other substance use comorbidities also known to be associated with cognition, such as nicotine use. The present study aimed to fill this gap and clarify the relationship between adolescent alcohol use and young adult cognition by accounting for both measured and unmeasured confounders. Design: A random effects model accounting for nesting in families was used to control for measured confounders. Next, co‐twin comparisons were conducted within the full sample and in monozygotic twin pairs (MZ) to control for unmeasured genetic and environmental confounders shared by co‐twins. Participants/Setting: Participants were 812 individuals (58.6% female, 361 complete pairs, 146 MZ pairs) from the longitudinal FinnTwin12 study in Finland. Measurements Adolescent alcohol use was indexed with measures of frequency of use and intoxication averaged across ages 14 and 17. Cognitive outcomes were measured at average age 22 and included Trail Making Test, California Stroop test, Wechsler Adult Intelligence subtests (Vocabulary, Block Design, Digit Symbol), Digit Span subtest of Wechsler Memory Scale, Mental Rotation Test and Object Location Memory test. Covariates included sex, parental education, general cognitive ability, current alcohol use and nicotine use. Findings Greater frequency of alcohol use and frequency of intoxication across adolescence was associated with decreased vocabulary scores in the co‐twin control [freq: stnd beta = −0.12, 95% confidence interval (CI) = −0.234, −0.013] and MZ only co‐twin control models (freq: stnd beta = −0.305, 95% CI = –0.523, −0.087; intox: stnd beta = −0.301, 95% CI = ‐0.528, −0.074). Conclusions: In Finland, there appears to be little evidence that adolescent alcohol use causes cognitive deficits in young adulthood, except modest evidence for association of higher adolescent alcohol use with lower young adult vocabulary scores. [ABSTRACT FROM AUTHOR]

Background: As populations are aging, it needs to be ensured that valid depression rating scales are available across old adulthood. Center for Epidemiological Studies-Depression scale (CES-D) is a common depression rating scale, however, few studies have assessed its validity in individuals with age over 90 and/or cognitive impairment. We examined the factor structures of 20-, 15-, and 8-item CES-D scales, their measurement invariance for age and cognition, and associations with genetic risk of depression. Methods: Participants were from a population-based older Finnish Twin Cohort study including 71–79-year-olds from the MEMTWIN II (n = 1034 for exploratory and n = 664 for confirmatory factor analyses) and 90+ year-olds from the NONAGINTA (n = 134, confirmatory factor analyses) sub-studies. Associations of polygenic risk score of major depressive disorder (MDD-PRS) with CES-D scales were examined in MEMTWIN II. Results: Exploratory factor analyses (n = 1034) suggested four- (CES-D 20) and three-factor (CES-D 8) structures and these models fit well in confirmatory analyses (n = 664). Unidimensional models had good (CES-D 15 & 20) or fair fit (CES-D 8). Results supported scalar invariance of all CES-D versions for age and cognitive status. Higher MDD-PRS was associated with more depressive symptoms in different CES-D versions. Conclusions: Different CES-D versions are adequate for measuring depressive symptoms across age groups and cognitive spectrum in old age. Genetic risk of depression predicts depressive symptoms even in old age. [ABSTRACT FROM AUTHOR]

Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders. [ABSTRACT FROM AUTHOR]

Purpose: To examine age‐related macular degeneration (AMD) and retinal pigment epithelium (RPE)–Bruch's membrane (BrM) complex volume associations in monozygotic twin pairs. Methods: In this study, 106 elderly twins (53 twin pairs) from the Finnish Twin Cohort study were recruited. Each participant underwent dilated 35‐degree digital colour fundus photography (CFP), and spectral domain optical coherence tomography (OCT) and replied to a structured study questionnaire. The CFPs were graded according to the Age‐Related Eye Disease Study (AREDS) classification. The OCT images were segmented and volumetric data of the RPE‐BrM complex volume was calculated with the Orion™ software. The worse eye according to AREDS classification was used for the analysis. Results: Twenty‐nine (55%) of the twin pairs were discordant with regard to AREDS classification. Fourteen (26%) pairs were discordant with one twin participant having AMD (AREDS 2–4) and the other being unaffected (AREDS 1). Four (8%) pairs had one twin participant with intermediate or late AMD (AREDS 3–4) versus the other being unaffected (AREDS 1). The within‐pair polychoric correlation for AREDS was 0.605 (95% confidence interval 0.418–0.792). In multivariate analysis intermediate and late AMD as well as age associated with RPE‐BrM complex volume. RPE‐BrM complex volume showed a within twin pair correlation, r = 0.430 (95% confidence interval 0.172–0.688, p < 0.01). Conclusion: A substantial proportion of monozygotic twin pairs are discordant with regard to age‐related macular degeneration phenotype. RPE‐BrM complex volume associated with age and intermediate and late AMD. [ABSTRACT FROM AUTHOR]

Regular cigarette smoking and cannabis consumption are strongly positively related to each other, yet few studies explore their underlying variation and covariation. We evaluated the genetic and environmental decomposition of variance and covariance of these two traits in twin data from three countries with different social norms and legislation. Data from the Netherlands Twin Register, FinnTwin12/16, and the Minnesota Center for Twin Family Research (total N = 21,617) were analyzed in bivariate threshold models of lifetime regular smoking initiation (RSI) and lifetime cannabis initiation (CI). We ran unstratified models and models stratified by sex and country. Prevalence of RSI was lowest in the Netherlands and prevalence of CI was highest in Minnesota. In the unstratified model, genetic (A) and common environmental factors (C) contributed substantially to the liabilities of RSI (A = 0.47, C = 0.34) and CI (A = 0.28, C = 0.51). The two liabilities were significantly phenotypically (rP = 0.56), genetically (rA = 0.74), and environmentally correlated in the unstratified model (rC = 0.47and rE = 0.48, representing correlations between common and unique environmental factors). The magnitude of phenotypic correlation between liabilities varied by country but not sex (Minnesota rP ~ 0.70, Netherlands rP ~ 0.59, Finland rP ~ 0.45). Comparisons of decomposed correlations could not be reliably tested in the stratified models. The prevalence and association of RSI and CI vary by sex and country. These two behaviors are correlated because there is genetic and environmental overlap between their underlying latent liabilities. There is heterogeneity in the genetic architecture of these traits across country. [ABSTRACT FROM AUTHOR]

Background: Separating with close siblings and leaving the parental home at an early age represents a major life event for an adolescent (reflected by age at separation in a twin pair) and may predispose them to poor mental health. This study aims to examine the association of age at separation and residential mobility on depressive symptoms in late adolescence and young adulthood and to explore possible underlying genetic effects. Methods: Residential mobility consisted of the number and total distance of moves before age 17. Based on 3071 twins from the FinnTwin12 cohort, we used linear regression to assess the association of age at separation and residential mobility with General Behavior Inventory (GBI) scores at age 17 and in young adulthood. A higher GBI score indicated more depressive symptoms occurred. Then, the mixed model for repeated measures (MMRM) was used to visualize the scores' trajectory and test the associations, controlling for "baseline" state. Twin analyses with a bivariate cross-lagged path model were performed between the difference in GBI scores, between cotwins, and separation status for the potential genetic influence. Results: Compared to twins separated before age 17, twins who separated later had significantly lower GBI scores at age 17 and in young adulthood. In MMRM, separation at a later age and a higher number of moves were associated with a higher GBI score in young adulthood. A small genetic effect was detected wherein GBI within-pair differences at age 17 were associated with separation status before age 22 (coefficient: 0.01). Conclusion: The study provides valid evidence about the influence of siblings and family on depressive symptoms in later adolescence and young adulthood while finding some evidence for a reverse direction effect. This suggests more caution in the interpretation of results. A strong association between residential mobility and depressive symptoms was affirmed, although further detailed research is needed. [ABSTRACT FROM AUTHOR]

Background: Forty percent of patients with aneurysmatic subarachnoid hemorrhage (aSAH) develop acute hydrocephalus requiring treatment with cerebrospinal fluid (CSF) drainage. CSF cell parameters are used in the diagnosis of nosocomial infections but also reflect sterile inflammation after aSAH. We aimed to study the temporal changes in CSF parameters and compare external ventricular drain (EVD)–derived and lumbar spinal drain–derived samples. Methods: We retrospectively identified consecutive patients with aSAH treated at our neurointensive care unit between January 2014 and May 2019. We mapped the temporal changes in CSF leucocyte count, erythrocyte count, cell ratio, and cell index during the first 19 days after aSAH separately for EVD-derived and spinal drain–derived samples. We compared the sample sources using a linear mixed model, controlling for repeated sampling. Results: We included 1360 CSF samples from 197 patients in the analyses. In EVD-derived samples, the CSF leucocyte count peaked at days 4–5 after aSAH, reaching a median of 225 × 106 (interquartile range [IQR] 64–618 × 106). The cell ratio and index peaked at 8–9 days (0.90% [IQR 0.35–1.98%] and 2.71 [IQR 1.25–6.73], respectively). In spinal drain–derived samples, the leucocyte count peaked at days 6–7, reaching a median of 238 × 106 (IQR 60–396 × 106). The cell ratio and index peaked at 14–15 days (4.12% [IQR 0.63–10.61%]) and 12–13 days after aSAH (8.84 [IQR 3.73–18.84]), respectively. Compared to EVD-derived samples, the leucocyte count was significantly higher in spinal drain–derived samples at days 6–17, and the cell ratio as well as the cell index was significantly higher in spinal drain–derived samples compared to EVD samples at days 10–15. Conclusions: CSF cell parameters undergo dynamic temporal changes after aSAH. CSF samples from different CSF compartments are not comparable. [ABSTRACT FROM AUTHOR]

Purpose: High levels of physical activity have been documented in eating disorder patients. Our aim was to examine whether adolescent leisure-time physical activity is prospectively associated with eating disorders in adolescence and young adulthood. Methods: Finnish twins born in 1983–1987 reported their physical activity frequency at ages 12, 14, and 17. A subsample of participants underwent structured, retrospective interviews for eating disorders at the mean age of 22.4 years. Associations between female twins' physical activity and future eating disorders (571–683 twins/wave) were investigated with the Cox proportional hazards model. To illustrate the physical activity similarity of the co-twins in a twin pair, we used cross-tabulation of eating disorder–discordant twin pairs (13–24 pairs/wave). Results: After adjusting for several covariates, we found no statistically significant longitudinal association between physical activity and eating disorders. This applied when all eating disorders were combined but also when assessed separately as restrictive and non-restrictive eating disorders. Co-twins' physical activity in adolescence tended to be similar irrespective of their future eating disorder, supporting the results of the regression analysis. Conclusion: We observed no evidence of adolescent physical activity frequency being prospectively associated with eating disorders in female twins. Further longitudinal studies with larger sample sizes and more detailed physical activity data are needed. Level of evidence: III, evidence obtained from cohort or case–control analytic studies. [ABSTRACT FROM AUTHOR]

Background: Machine learning (ML) classifiers are increasingly used for predicting cardiovascular disease (CVD) and related risk factors using omics data, although these outcomes often exhibit categorical nature and class imbalances. However, little is known about which ML classifier, omics data, or upstream dimension reduction strategy has the strongest influence on prediction quality in such settings. Our study aimed to illustrate and compare different machine learning strategies to predict CVD risk factors under different scenarios. Methods: We compared the use of six ML classifiers in predicting CVD risk factors using blood-derived metabolomics, epigenetics and transcriptomics data. Upstream omic dimension reduction was performed using either unsupervised or semi-supervised autoencoders, whose downstream ML classifier performance we compared. CVD risk factors included systolic and diastolic blood pressure measurements and ultrasound-based biomarkers of left ventricular diastolic dysfunction (LVDD; E/e' ratio, E/A ratio, LAVI) collected from 1,249 Finnish participants, of which 80% were used for model fitting. We predicted individuals with low, high or average levels of CVD risk factors, the latter class being the most common. We constructed multi-omic predictions using a meta-learner that weighted single-omic predictions. Model performance comparisons were based on the F1 score. Finally, we investigated whether learned omic representations from pre-trained semi-supervised autoencoders could improve outcome prediction in an external cohort using transfer learning. Results: Depending on the ML classifier or omic used, the quality of single-omic predictions varied. Multi-omics predictions outperformed single-omics predictions in most cases, particularly in the prediction of individuals with high or low CVD risk factor levels. Semi-supervised autoencoders improved downstream predictions compared to the use of unsupervised autoencoders. In addition, median gains in Area Under the Curve by transfer learning compared to modelling from scratch ranged from 0.09 to 0.14 and 0.07 to 0.11 units for transcriptomic and metabolomic data, respectively. Conclusions: By illustrating the use of different machine learning strategies in different scenarios, our study provides a platform for researchers to evaluate how the choice of omics, ML classifiers, and dimension reduction can influence the quality of CVD risk factor predictions. [ABSTRACT FROM AUTHOR]

Background: Personalized interventions aiming to increase physical activity in individuals are effective. However, from a public health perspective, it would be important to stimulate physical activity in larger groups of people who share the vulnerability to be physically inactive throughout adulthood. To find these high-risk groups, we identified 36-year leisure-time physical activity profiles from young adulthood to late midlife in females and males. Moreover, we uncovered which anthropometric-, demographic-, lifestyle-, and health-related characteristics were associated with these physical activity profiles. Methods: We included 2,778 females and 1,938 males from the population-based older Finnish Twin Cohort Study, who responded to health and behavior surveys at the mean ages of 24, 30, 40 and 60. Latent profile analysis was used to identify longitudinal leisure-time physical activity profiles. Results: We found five longitudinal leisure-time physical activity profiles for both females and males. Females' profiles were: 1) Low increasing moderate (29%), 2) Moderate stable (23%), 3) Very low increasing low (20%), 4) Low stable (20%) and 5) High increasing high (9%). Males' profiles were: 1) Low increasing moderate (29%), 2) Low stable very low (26%), 3) Moderate decreasing low (21%), 4) High fluctuating high (17%) and 5) Very low stable (8%). In both females and males, lower leisure-time physical activity profiles were associated with lower education, higher body mass index, smoking, poorer perceived health, higher sedentary time, high blood pressure, and a higher risk for type 2 diabetes. Furthermore, lower leisure-time physical activity was linked to a higher risk of depression in females. Conclusions: We found several longitudinal leisure-time physical activity profiles with unique changes in both sexes. Fewer profiles in females than in males remained or became low physically active during the 36-year follow-up. We observed that lower education, higher body mass index, and more smoking already in young adulthood were associated with low leisure-time physical activity profiles. However, the fact that several longitudinal profiles demonstrated a change in their physical activity behavior over time implies the potential for public health interventions to improve leisure-time physical activity levels. [ABSTRACT FROM AUTHOR]

Background We used a polygenic score for hand grip strength (PGS HGS) to investigate whether genetic predisposition for higher muscle strength predicts age-related noncommunicable diseases, survival from acute adverse health events, and mortality. Methods This study consisted of 342 443 Finnish biobank participants from FinnGen Data Freeze 10 (53% women) aged 40–108 with combined genotype and health registry data. Associations between PGS HGS and a total of 27 clinical endpoints were explored with linear or Cox regression models. Results A higher PGS HGS was associated with a reduced risk of selected common noncommunicable diseases and mortality by 2%–10%. The risk for these medical conditions decreased by 5%–23% for participants in the highest PGS HGS quintile compared to those in the lowest PGS HGS quintile. A 1 standard deviation (SD) increase in the PGS HGS predicted a lower body mass index (β = −0.112 kg/m2, standard error [ SE ] = 0.017, p  = 1.69E-11) in women but not in men (β = 0.004 kg/m2, p  = .768). PGS HGS was not associated with better survival after acute adverse health events compared to the nondiseased period. Conclusions The genotype that supports higher muscle strength appears to protect against future health adversities, albeit with modest effect sizes. Further research is needed to investigate whether or how a favorable lifestyle modifies this intrinsic capacity to resist diseases, and if the impacts of lifestyle behavior on health differs due to genetic predisposition for muscle strength. [ABSTRACT FROM AUTHOR]

Aim: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole‐body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight. Methods: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co‐twins 7.6 kg/m2; eight female pairs). Ten pairs completed the 6‐month long training intervention. We measured lumbar vertebral and femoral BM insulin‐stimulated glucose uptake (GU) using 18F‐FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers. Results: At baseline, heavier co‐twins had higher lumbar vertebral BM GU (p <.001) and lower bone turnover markers (all p <.01) compared with leaner co‐twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole‐body insulin sensitivity, aerobic capacity (both p <.05) and femoral BM GU (p =.008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p =.02), as GU tended to decrease in heavier co‐twins (p =.06) while there was no change in leaner co‐twins. Conclusions: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co‐twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity. [ABSTRACT FROM AUTHOR]

Background: The association of sleep bruxism with mortality has not been studied. Objectives: Altogether 12 040 subjects from the nationwide Finnish twin cohort were included in the analyses. We examined whether self‐reported sleep bruxism is associated with increased risk of mortality, and if so, whether the effect is independent of known common risk factors. The time span of the follow‐up was 30 years. Methods: Cox proportional hazards regression models (Hazard Ratios and their 95% Confidence Intervals) adjusted by age, sex and covariates were used to assess the effect of baseline bruxism status in 1990 on future mortality in 1990–2020. Results: The risk of mortality among all participants (n = 12 040), independent of missing covariates and adjusted by age and sex, was 40% higher in weekly bruxers than in never bruxers (HR 1.40, 95% CI 1.16–1.68, p <.001). However, when adjusted by all studied covariates, (n = 11 427) the risk was no longer observed (HR 1.04, 95% CI 0.86–1.25, p =.717). Despite the overall lack of between bruxism and mortality after adjustment for covariates, we examined the cause‐specific risks for major cause‐of‐death groups. There were no substantial associations of weekly bruxism with major disease outcomes by the fully adjusted hazard ratios for them. Conclusion: Bruxism does not kill—in line with its definition of being rather a behaviour (with all its phenotypes) than a disease. [ABSTRACT FROM AUTHOR]

Background: Due to different assessment modes employed, a clear picture of the prevalence of sleep bruxism across time cannot be formed. Moreover, studies on the persistent or fluctuating nature of sleep bruxism have yielded divergent and even contradictory results. The aim of the present study was to evaluate in a nationwide twin cohort whether self‐reported sleep bruxism was correlated longitudinally, pairwise and cross‐twin over a 20‐year period. Objectives: Self‐reported bruxism was assessed in 1990 and 2011 by mailed questionnaires in the Finnish Twin Cohort study of same‐sex twins born 1945–1957. Methods: We assessed the phenotypic stability over time for all participating individuals (n = 4992). Among zygosity verified pairs (n = 516 MZ and n = 837 DZ), we estimated the cross‐sectional zygosity correlations and the zygosity‐specific cross‐twin cross‐time correlations. Results: Reported bruxism appeared rather persistent over time without significant difference regarding zygosity. The overall phenotypic longitudinal correlation was 0.540 and somewhat higher in men (0.596) than in women (0.507). Pairwise trait correlations in 1990 and 2011 were higher in MZ than in DZ pairs. The cross‐twin cross‐time correlations were higher in MZ twins than in DZ twins, but less than the cross‐sectional MZ and DZ pairwise correlations. Conclusions: The higher correlation of reported sleep bruxism in the cross‐twin cross‐time analyses in MZ than in DZ pairs implies a genetic background for bruxism persistence. Also, bruxism over time in individual twins appears to be fairly persistent and somewhat higher in men than women. [ABSTRACT FROM AUTHOR]

Background: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remains underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein–BMI trajectory associations in adolescents and adults and how these connect to other omics layers. Methods: Our study included two cohorts of longitudinally followed twins: FinnTwin12 (N = 651) and the Netherlands Twin Register (NTR) (N = 665). Follow-up comprised 4 BMI measurements over approximately 6 (NTR: 23–27 years old) to 10 years (FinnTwin12: 12–22 years old), with omics data collected at the last BMI measurement. BMI changes were calculated in latent growth curve models. Mixed-effects models were used to quantify the associations between the abundance of 439 plasma proteins with BMI at blood sampling and changes in BMI. In FinnTwin12, the sources of genetic and environmental variation underlying the protein abundances were quantified by twin models, as were the associations of proteins with BMI and BMI changes. In NTR, we investigated the association of gene expression of genes encoding proteins identified in FinnTwin12 with BMI and changes in BMI. We linked identified proteins and their coding genes to plasma metabolites and polygenic risk scores (PRS) applying mixed-effects models and correlation networks. Results: We identified 66 and 14 proteins associated with BMI at blood sampling and changes in BMI, respectively. The average heritability of these proteins was 35%. Of the 66 BMI-protein associations, 43 and 12 showed genetic and environmental correlations, respectively, including 8 proteins showing both. Similarly, we observed 7 and 3 genetic and environmental correlations between changes in BMI and protein abundance, respectively. S100A8 gene expression was associated with BMI at blood sampling, and the PRG4 and CFI genes were associated with BMI changes. Proteins showed strong connections with metabolites and PRSs, but we observed no multi-omics connections among gene expression and other omics layers. Conclusions: Associations between the proteome and BMI trajectories are characterized by shared genetic, environmental, and metabolic etiologies. We observed few gene-protein pairs associated with BMI or changes in BMI at the proteome and transcriptome levels. [ABSTRACT FROM AUTHOR]

Background: Research on device-based physical activity in the oldest-old adults is scarce. We examined accelerometer-measured physical activity and sedentary behavior in nonagenarians. We also investigated how the accelerometer characteristics associate with nonagenarians' self-reported physical activity, anthropometric, sociodemographic, health and cognitive characteristics. Methods: Nonagenarians from a population-based cohort study (N = 38, mean age 91.2) used accelerometers during the waking hours for seven days. They also participated in a health survey and cognitive telephone interview. The Wald test and Pearson and polyserial correlations were used to analyze the data. Results: The participants' average day consisted of 2931 steps, 11 minutes of moderate-to-vigorous physical activity and 13.6 hours of sedentary time. Physical activity bouts less than 3 minutes per day and sedentary time bouts of 20–60 minutes per day were the most common. No sex differences were found. Many accelerometer-measured and self-reported physical activity characteristics correlated positively (correlations ≥0.34, p-values <0.05). The low levels of many accelerometer-measured physical activity characteristics associated with low education (correlations ≥0.25, p-values <0.05), dizziness (correlations ≤-0.42, p-values <0.01) and fear of falling (correlations ≤-0.45, p-values <0.01). Fear of falling was also associated with accelerometer-measured sedentary behavior characteristics (correlations -0.42 or ≥0.43). Conclusions: Nonagenarians were mostly sedentary and low in physical activity, but individual variability existed. Accelerometer-measured and self-reported physical activity had a good consistency. Education, dizziness and fear of falling were consistently related to accelerometer-measured characteristics in nonagenarians. [ABSTRACT FROM AUTHOR]

Objective: The relationship between obesity and mental health is complex and is moderated by the level of obesity, age, sex, and social and genetic factors. In the current study, we used a unique co-twin control design, with twin pairs discordant for body mass index (BMI), to control for shared genetic and environmental effects between obesity and several dimensions of mental health. Methods: We studied 74 monozygotic (MZ) twin pairs, of whom 36 were BMI-discordant (intra-pair difference in BMI ≥ 3 kg/m2), and 77 dizygotic (DZ) twin pairs (46 BMI-discordant). We assessed subjective health, especially mental health and mental well-being (depression, anxiety, self-esteem, health-related quality of life, life satisfaction, and social well-being) through questionnaires. Results: Heavier MZ co-twins from BMI-discordant pairs had poorer general health (58.8±3.0 vs. 72.4±3.8, P = 0.001, FDR = 0.017 on a scale from 0 to 100 where higher scores indicate more positive results), physical functioning (90.3±1.1 vs. 95.5±2.2, P = 0.024, FDR = 0.122), energy levels (55.6±3.4 vs. 66.6±3.3, P = 0.013, FDR = 0.109), and emotional well-being (65.9±3.2 vs. 75.4±2.9, P = 0.031, FDR = 0.122), as well as a tendency for depressive symptoms (8.4±1.3 vs. 5.6±0.9, P = 0.071, FDR = 0.166) compared to their leaner co-twins. Heavier DZ co-twins had poorer total physical well-being (91.6±1.9 vs. 95.6±1.0, P = 0.035, FDR = 0.356) and more depressive symptoms (4.3±0.9 vs. 2.4±0.5, P = 0.016, FDR = 0.345 on a scale from 0 to 63 where lower scores indicate fewer depressive symptoms) than their leaner co-twins. Association analyses, using all twin pairs, confirmed that higher BMI within pairs linked to general health, physical functioning and depressive symptoms. No association was found between BMI and anxiety, self-esteem, life satisfaction, or social well-being. Conclusions: In conclusion, this study underscores the notable association between elevated BMI and physical well-being and to a lesser extent between elevated BMI and depressive symptoms, while revealing no discernible connections with anxiety, self-esteem, life satisfaction, or social well-being. [ABSTRACT FROM AUTHOR]

Objective: This study investigated 36‐year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within‐pair ΔBMI ≥ 3 kg/m2). Methods: Together, 3227 like‐sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<−2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms. Results: In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co‐twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co‐twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3–4.8). Conclusions: Categorizing BMI as below, within, or above polygenic risk score‐predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity. [ABSTRACT FROM AUTHOR]

Background: Both genetic and environmental influences have been shown to contribute to the association between physical activity and overall academic performance. The authors examined whether leisure-time physical activity (LTPA) shares genetic and environmental variances between spelling, essay writing, reading aloud, reading comprehension, and mathematics in early adolescence. Moreover, they investigated whether genetic polymorphisms associated with physical activity behavior affect these academic skills. Methods: Participants were 12-year-old Finnish twins (n = 4356–4370 twins/academic skill, 49% girls). Academic skills were assessed by teachers, and LTPA was self-reported. Polygenic scores for physical activity behavior were constructed from the UK Biobank. Quantitative genetic modeling and linear regression models were used to analyze the data. Results: The trait correlations between LTPA and academic skills were significant but weak (r =.05–.08). The highest trait correlation was found between LTPA and mathematics. A significant genetic correlation was revealed between LTPA and essay writing (rA =.14). Regarding polygenic scores of physical activity, the highest correlations were found with reading comprehension, spelling, and essay writing, but these results only approached statistical significance (P values =.09–.15). Conclusions: The authors' results suggest that reading and writing are the academic skills that most likely share a common genetic background with LTPA. [ABSTRACT FROM AUTHOR]

Background: Puberty is a highly heritable and variable trait, with environmental factors having a role in its eventual timing and development. Early and late pubertal onset are both associated with various diseases developing later in life, and epigenetic characterisation of pubertal timing and development could lead to important insights. Blood DNA methylation, reacting to both genotype and environment, has been associated with puberty; however, such studies are relatively scarce. We investigated peripheral blood DNA methylation profiles (using Illumina 450 K and EPIC platforms) of 1539 young adult Finnish twins associated with pubertal development scale (PDS) at ages 12 and 14 as well as pubertal age (PA). Results: Fixed effect meta-analysis of the two platforms on 347,521 CpGs in common identified 58 CpG sites associated (p < 1 × 10−5) with either PDS or PA. All four CpGs associated with PA and 45 CpGs associated with PDS were sex-specific. Thirteen CpGs had a high heritability (h2: 0.51–0.98), while one CpG site (mapped to GET4) had a high shared environmental component accounting for 68% of the overall variance in methylation at the site. Utilising twin discordance analysis, we found 6 CpG sites (5 associated with PDS and 1 with PA) that had an environmentally driven association with puberty. Furthermore, genes with PDS- or PA-associated CpGs were consistently linked to various developmental processes and diseases such as breast, prostate and ovarian cancer, while methylation quantitative trait loci of associated CpG sites were enriched in immune pathways developing during puberty. Conclusions: By identifying puberty-associated DNA methylation sites and examining the effects of sex, environment and genetics, we shed light on the intricate interplay between environment and genetics in the context of puberty. Through our comprehensive analysis, we not only deepen the understanding of the significance of both genetic and environmental factors in the complex processes of puberty and its timing, but also gain insights into potential links with disease risks. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: There is increasing evidence for the existence of shared genetic predictors of metabolic traits and neurodegenerative disease. We previously observed a U-shaped association between fasting insulin in middle-aged women and dementia up to 34 years later. In the present study, we performed genome-wide association (GWA) analyses for fasting serum insulin in European children with a focus on variants associated with the tails of the insulin distribution. Methods: Genotyping was successful in 2825 children aged 2–14 years at the time of insulin measurement. Because insulin levels vary during childhood, GWA analyses were based on age- and sex-specific z scores. Five percentile ranks of z-insulin were selected and modelled using logistic regression, i.e. the 15th, 25th, 50th, 75th and 85th percentile ranks (P15–P85). Additive genetic models were adjusted for age, sex, BMI, survey year, survey country and principal components derived from genetic data to account for ethnic heterogeneity. Quantile regression was used to determine whether associations with variants identified by GWA analyses differed across quantiles of log-insulin. Results: A variant in the SLC28A1 gene (rs2122859) was associated with the 85th percentile rank of the insulin z score (P85, p value=3×10−8). Two variants associated with low z-insulin (P15, p value <5×10−6) were located on the RBFOX1 and SH3RF3 genes. These genes have previously been associated with both metabolic traits and dementia phenotypes. While variants associated with P50 showed stable associations across the insulin spectrum, we found that associations with variants identified through GWA analyses of P15 and P85 varied across quantiles of log-insulin. Conclusions/interpretation: The above results support the notion of a shared genetic architecture for dementia and metabolic traits. Our approach identified genetic variants that were associated with the tails of the insulin spectrum only. Because traditional heritability estimates assume that genetic effects are constant throughout the phenotype distribution, the new findings may have implications for understanding the discrepancy in heritability estimates from GWA and family studies and for the study of U-shaped biomarker–disease associations. [ABSTRACT FROM AUTHOR]

Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trøndelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m2, 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors. [ABSTRACT FROM AUTHOR]

Background Measures of biological aging range from DNA methylation (DNAm)-based estimates to measures of physical abilities. The purpose of this study was to compare DNAm- and physical functioning-based measures of biological aging in predicting mortality. Methods We studied 63- to 76-year-old women (N = 395) from the Finnish Twin Study on Aging (FITSA). Participants' biological age (epigenetic clocks DNAm GrimAge and DunedinPACE) was estimated using blood DNAm data. Tests of physical functioning conducted under standardized laboratory conditions included the Timed Up and Go (TUG) test and 10-m walk test. Mortality hazard ratios were calculated per every 1 standard deviation (SD) increase in the predictor. Cox regression models were conducted for individuals and twin pairs, the latter controlling for underlying genetic effects. The models were adjusted for known lifestyle predictors of mortality. Results During the follow-up period (mean 17.0 years, range 0.2–20.3), 187 participants died. In both the individual-based and pairwise analyses, GrimAge and both functional biomarkers of aging were associated with mortality independent of family relatedness, chronological age, physical activity, body mass index, smoking, education, or chronic diseases. In a model including both the DNAm-based measures and functional biomarkers of aging, GrimAge and TUG remained predictive. Conclusions The findings suggest that DNAm GrimAge and the TUG test are strong predictors of mortality independent of each others and genetic influences. DNAm-based measures and functional tests capture different aspects of the aging process and thus complement each other as measures of biological aging in predicting mortality. [ABSTRACT FROM AUTHOR]

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset (~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions. Preadipocytes contribute to the pro-inflammatory environment in obesity, via unknown mechanisms. Here, comparing monozygotic twin pairs, the authors show that co-accessibility of chromatin in preadipocytes is altered in siblings with higher compared to lower BMI, and that variants in these regions contribute to systemic inflammation via interactions with BMI. [ABSTRACT FROM AUTHOR]

The UK Biobank study on chronotype and mortality suggested small increases of all-cause and cardiovascular mortality in a 6.5-year follow-up. Our aim was to constructively replicate findings from it in a longer follow-up. A questionnaire was administered to the population-based adult Finnish Twin Cohort in 1981 (response rate 84%). The study population included 23 854 participants who replied to the question: "Try to assess to what extent you are a morning person or an evening person," with four response alternatives (anchored from "clearly a morning person" to "clearly an evening person"). Vital status and cause of death data were provided by nationwide registers up to the end of 2018. Hazard ratios for mortality were computed based on 8728 deaths. Adjustments were made for education, alcohol, smoking, BMI, and sleep duration. The covariate adjusted model showed a 9% increase of all-cause mortality for the evening-type group (HR = 1.09, 95% CI 1.01–1.18), with attenuation mainly due to smoking and alcohol. Their importance was highlighted by observing no increased mortality among non-smokers who were at most light drinkers. There was no increase in any cause-specific mortality. Our results suggest that there is little or no independent contribution of chronotype to mortality. [ABSTRACT FROM AUTHOR]

Introduction: Assortative mating refers describes a phenomenon in which individuals with similar phenotypic traits are more likely to mate and reproduce with each other; i.e. assortative mating occurs when individuals choose partners based on their similarity or dissimilarity in certain traits. to patterns of non-randommating of spouses leading to phenotypic resemblance. There are various theories about the its underlying mechanisms, which have different genetic consequences. Methods: Weanalyzed examined two possible mechanisms underlying assortative mating - phenotypic assortment and social homogamy - for educational attainment in two countries utilizing data of mono- and dizygotic twins and their spouses (1,451 Finnish and 1,616 Dutch twin-spouse pairs). Results: The spousal correlations were 0.51 in Finland and 0.45 in the Netherlands, to which phenotypic assortment contributed 0.35 and 0.30, and social homogamy 0.16 and 0.15, respectively. Conclusion: Both social homogamy and phenotypic assortment are important processes in spouse selection in Finland and the Netherlands. In both countries, phenotypic assortment contributes to a greater degree to the similarity of spouses than social homogamy. [ABSTRACT FROM AUTHOR]

Although we found no genetic correlation between baseline BMI and alcohol consumption, a genetic correlation associating baseline BMI with a change in alcohol consumption was observed in both men and women. The aims of the current study were therefore (1) to study the relationship between BMI and alcohol consumption trajectories, (2) to highlight the genetic and environmental components underlying changes in BMI and alcohol consumption, and (3) to investigate possible genetic and environmental correlations between BMI and alcohol consumption trajectories. Obesity and heavy alcohol consumption are major public health issues worldwide due to their high and increasing prevalence in recent decades [[1]]. These results support the existence of complex genetic architectures influencing (1) alcohol consumption and changes in alcohol consumption, (2) BMI with changes in BMI, and (3) BMI intercept with alcohol-related behavior over time. [Extracted from the article]

Breast cancer is highly prevalent yet a more complete understanding of the interplay between genes and probable environmental risk factors, such as night work, remains lagging. Using a discordant twin pair design, we examined the association between night shift work and breast cancer risk, controlling for familial confounding. Shift work pattern was prospectively assessed by mailed questionnaires among 5,781 female twins from the Older Finnish Twin Cohort. Over the study period (1990–2018), 407 incident breast cancer cases were recorded using the Finnish Cancer Registry. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for potential confounders. Within-pair co-twin analyses were employed in 57 pairs to account for potential familial confounding. Compared to women who worked days only, women with shift work that included night shifts had a 1.58-fold higher risk of breast cancer (HR = 1.58; 95%CI, 1.16–2.15, highest among the youngest women i.e. born 1950–1957, HR = 2.08; 95%CI, 1.32–3.28), whereas 2-shift workers not including night shifts, did not (HR = 0.84; 95%CI, 0.59–1.21). Women with longer sleep (average sleep duration > 8 h/night) appeared at greatest risk of breast cancer if they worked night shifts (HR = 2.91; 95%CI, 1.55–5.46; Pintx=0.32). Results did not vary by chronotype (Pintx=0.74). Co-twin analyses, though with limited power, suggested that night work may be associated with breast cancer risk independent of early environmental and genetic factors. These results confirm a previously described association between night shift work and breast cancer risk. Genetic influences only partially explain these associations. [ABSTRACT FROM AUTHOR]

Parents' alcohol use is associated with alcohol use of their adolescent offspring, but does this association extend to the adulthood of the offspring? We examined associations of paternal and maternal problem drinking with lifetime problem drinking of their adult offspring prospectively assessed in a population-based Finnish twin-family cohort (FinnTwin16). Problem drinking (Malmö-modified Michigan Alcoholism Screening Test) was self-reported separately by mothers and fathers when their children were 16. The children reported on an extended lifetime version of the same measure during their mid-twenties (21-28 years) and mid-thirties (31-37 years). 1235 sons and 1461 daughters in mid-twenties and 991 sons and 1278 daughters in mid-thirties had complete data. Correlations between fathers' and their adult children's problem drinking ranged from.12 to.18. For mothers and their adult children, these correlations ranged from.09 to.14. In multivariate models, adjustment for potential confounders had little effect on the observed associations. In this study, parental problem drinking was modestly associated with lifetime problem drinking of their adult children. This association could be detected even when the children had reached the fourth decade of life. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) is said to be beneficial to many bodily functions. However, the effects of PA in the brain are still inadequately known. The authors aimed to uncover possible brain modulation linked with PA. Here, they combine 4 of their studies with monozygotic twins, who were within-pair discordant in PA for a minimum of 1 year. Methods: The authors performed brain imaging, brain electrophysiology, and cardiovascular and body composition assessments, and collected questionnaire-based data. The present synopsis elucidates the differences associated with differing PA history in conditions without genetic variability. They present new structural and electrophysiological results. Participants, healthy, 45 male monozygotic twins (mean age 34.5 [1.5] y) differed in aerobic capacity and fat percentage (P < .001). Results: More active co-twins showed larger gray matter volumes in striatal, prefrontal, and hippocampal regions, and smaller gray matter volumes in the anterior cingulate area than less active co-twins. Functionally, visual and somatosensory automatic change detection processes differed between more and less active co-twins. Conclusions: In monozygotic twins, who differed in their PA history, differences were observed in identifiable anatomic brain locations involved with motor control and memory functions, as well as in electrophysiological measures detecting brain's automatic processes. Better aerobic capacity may modify brain morphology and sensory function. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine associations of early childhood physical fitness and physical activity (PA) with PA during later childhood/early adolescence while accounting for gender differences. Methods: We selected data of N = 4329 children from the IDEFICS/I. Family cohort (age 2.4–11.7 years) with data on baseline fitness and accelerometer measurements. At baseline, physical fitness tests were conducted including Flamingo balance, Backsaver sit and reach, Handgrip strength, Standing Long Jump, 40-m sprint and 20-m Shuttle run (to estimate cardio-respiratory fitness levels). PA was measured with Actigraph accelerometers over 3 days at baseline (ActiTrainer or GT1M) and 7 days at follow-up (GT3X). Evenson cutpoints were used to determine moderate-to-vigorous PA (MVPA) time, and children with ≥60mins/day of average MVPA were deemed as having met WHO guidelines at baseline and follow-up. Linear and logistic regressions were performed to examine longitudinal associations between meeting WHO guidelines, MVPA, and physical fitness tests at baseline with meeting WHO guidelines and MVPA at follow-up. Models were conducted on the entire sample, the sex-stratified sample, and stratified by sex and pubertal status at follow-up. Results: Results showed that meeting WHO guidelines for MVPA at baseline was positively associated with MVPA (Standardized Beta (B) = 0.13, 95%CI:(5.6;11.1)) and meeting WHO guidelines at follow-up for the entire sample (OR = 2.1, 95%CI:(1.5; 3.14), and stratified by males (OR = 2.5, 95%CI:(1.5; 4.1)) and females (OR = 1.8, 95%CI:(1.0; 3.2)). This was also found for both male pre/early pubertal and pubertal groups but only in the female pre/early pubertal group, and not the female pubertal group (MVPA: B =.00, 95%CI:(− 6.1; 5.6), WHO: OR = 0.61, 95%CI:(0.23;1.6)). Models indicated that Standing Long jump, 40-m sprint, Shuttle run and Flamingo balance at baseline were associated with MVPA and meeting the guidelines at follow-up. Conclusions: Meeting WHO guidelines and certain fitness tests at baseline were strongly associated with MVPA and meeting WHO guidelines at follow-up, but this association varied with sex and pubertal status. Consequently, these findings underline the importance of ensuring sufficient physical activity in terms of quality and quantity for children at the earliest stages of life. Trial registration: ISRCTN62310987. [ABSTRACT FROM AUTHOR]

Summary: Background: Living in single parent and blended families or as an only child—compared to living in two‐parent biological families or with siblings, respectively—is associated with a higher body mass index (BMI) in cross‐sectional studies. However, longitudinal research addressing the children's BMI in this context is scarce. Further, little is known about the association between family structure and metabolic health. Objectives: This study aimed at investigating the association between both aspects of family structure with BMI and a metabolic score (MetS). Methods: Cross‐sectional data from 7804 children participating in the European multi‐center I.Family study (2013/2014) and longitudinal data from 5621 children who also participated previously in the IDEFICS study (2007–2010) were used. Family structure was assessed by a detailed interview. BMI z‐score and the MetS were based on measured anthropometry, blood pressure, high‐density lipoprotein, blood glucose, and triglycerides. Linear regressions were performed to model associations between family structure with BMI and MetS. Results: Children from single‐parent families had higher BMI z‐scores in the cross‐sectional (β = 0.09, 95% confidence interval [CI]: 0.001 to 0.18) and longitudinal analyses compared to those from two‐parent families. Cross‐sectionally, the number of siblings was associated with lower BMI z‐scores (β = −0.07, 95% CI: −0.10 to −0.03) and lower MetS (β = −0.14, 95% CI: −0.26 to −0.01). Longitudinally, only children between baseline and follow‐up had higher BMI z‐scores at follow‐up (β = 0.07, 95% CI: 0.01 to 0.14) compared to stable siblings. Conclusion: Obesity prevention measures should focus on single‐parent households and families with an only child. [ABSTRACT FROM AUTHOR]

Background: Obesity is a heritable complex phenotype that can increase the risk of age‐related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various "epigenetic clocks." Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely correlates with mortality. Objectives: We aimed to assess the cross‐sectional association of body mass index (BMI) with age acceleration in twins to limit confounding by genetics and shared environment. Methods and results: Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twin pairs, and DNAm was measured using the Illumina 450K array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p‐value = 6.1 × 10–12) per one‐unit BMI increase. Additionally, heavier twins in a BMI‐discordant MZ twin pair (ΔBMI >3 kg/m2) had an epigenetic age 5.2 months older than their lighter cotwin (p‐value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta‐analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p‐value = 4.1 × 10–25) from adjusted models. Conclusion: We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance. [ABSTRACT FROM AUTHOR]

DNA methylation-based age acceleration (DNAmAA) is associated with cancer, with both cancer tissue and blood showing increased DNAmAA. We aimed to investigate whether DNAmAA is associated with cancer risk within twin pairs discordant for cancer, and whether DNAmAA has the potential to serve as a biomarker for such. The study included 47 monozygotic and 48 same-sex-dizygotic cancer-discordant twin pairs from the Finnish Twin Cohort study with blood samples available between 17 and 31 years after the cancer diagnosis. We studied all cancers (95 pairs), then separately breast cancer (24 pairs) and all sites other than breast cancer (71 pairs). DNAmAA was calculated for seven models: Horvath, Horvath intrinsic epigenetic age acceleration, Hannum, Hannum intrinsic epigenetic age acceleration, Hannum extrinsic epigenetic age acceleration, PhenoAge and GrimAge. Within-pair differences in DNAmAA were analyzed by paired t tests and linear regression. Twin pairs sampled before cancer diagnosis did not differ significantly in DNAmAA. However, the within-pair differences in DNAmAA before cancer diagnosis increased significantly the closer the cancer diagnosis was, and this acceleration extended for years after the diagnosis. Pairs sampled after the diagnosis differed for DNAmAA with the Horvath models capturing cancer diagnosis-associated DNAmAA across all three cancer groupings. The results suggest that DNAmAA in blood is associated with cancer diagnosis. This may be due to epigenetic alterations in relation to cancer, its treatment or associated lifestyle changes. Based on the current study, the biomarker potential of DNAmAA in blood appears to be limited. [ABSTRACT FROM AUTHOR]

Depression is a heterogeneous mental health problem affecting millions worldwide, but a majority of individuals with depression do not experience relief from initial treatments. Therefore, we need to improve our understanding of the biology of depression. Metabolomic approaches, especially untargeted ones, can suggest new hypotheses for further exploring biological mechanisms. Using the FinnTwin12 cohort, a longitudinal Finnish population-based twin cohort, with data collected in adolescence and young adulthood including 725 blood plasma samples, we investigated associations between depression and 11 low–molecular weight metabolites (amino acids and ketone bodies). In linear regression models with the metabolite (measured at age 22) as the dependent variable and depression ratings (measured at age 12, 14, 17, or 22 from multiple raters) as independent variables [adjusted first for age, sex, body mass index (BMI), and additional covariates (later)], we initially identified a significant negative association of valine with depression. Upon further analyses, valine remained significantly negatively associated with depression cross-sectionally and over time [meta-analysis beta = −13.86, 95% CI (−18.48 to −9.25)]. Analyses of the other branchedchain amino acids showed a significant negative association of leucine with depression [meta-analysis beta = −9.24, 95% CI (−14.53 to −3.95)], while no association was observed between isoleucine and depression [meta-analysis beta = −0.95, 95% CI (−6.00 to 4.11)]. These exploratory epidemiologic findings support further investigations into the role of branched-chain amino acids in depression. [ABSTRACT FROM AUTHOR]

Genetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure‐time physical activity (LTPA) in early adult life is thus a powerful study design to investigate the associations between long‐term LTPA and indicators of health and wellbeing. We have identified 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long‐term LTPA discordant MZ twin pairs have participated in multi‐dimensional clinical examinations. Key findings highlight that compared with less active twins in such MZ twin pairs, the twins with higher long‐term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, and an increased number of large high‐density lipoprotein particles. The findings increase our understanding on the possible site‐specific and system‐level effects of long‐term LTPA. [ABSTRACT FROM AUTHOR]

Background: The sex gap in life expectancy has been narrowing in Finland over the past 4-5 decades; however, on average, women still live longer than men. Epigenetic clocks are markers for biological aging which predict life span. In this study, we examined the mediating role of lifestyle factors on the association between sex and biological aging in younger and older adults.Methods: Our sample consists of younger and older twins (21‒42 years, n = 1 477; 50‒76 years, n = 763) including 151 complete younger opposite-sex twin pairs (21‒30 years). Blood-based DNA methylation was used to compute epigenetic age acceleration by 4 epigenetic clocks as a measure of biological aging. Path modeling was used to study whether the association between sex and biological aging is mediated through lifestyle-related factors, that is, education, body mass index, smoking, alcohol use, and physical activity.Results: In comparison to women, men were biologically older and, in general, they had unhealthier life habits. The effect of sex on biological aging was partly mediated by body mass index and, in older twins, by smoking. Sex was directly associated with biological aging and the association was stronger in older twins.Conclusions: Previously reported sex differences in life span are also evident in biological aging. Declining smoking prevalence among men is a plausible explanation for the narrowing of the difference in life expectancy between the sexes. Data generated by the epigenetic clocks may help in estimating the effects of lifestyle and environmental factors on aging and in predicting aging in future generations. [ABSTRACT FROM AUTHOR]

Background: We sought to clarify the impact of adolescent alcohol misuse on adult physical health and subjective well‐being. To do so, we investigated both the direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction and the indirect effects on these outcomes attributable to subsequent alcohol problems. Method: The sample included 2733 twin pairs (32% monozygotic; 52% female) from the FinnTwin16 study. Adolescent alcohol misuse was a composite of frequency of drunkenness, frequency of alcohol use, and alcohol problems at ages 16, 17, and 18.5. The early midlife outcomes included somatic symptoms, self‐rated health, and life satisfaction at age 34. The mediators examined as part of the indirect effect analyses included alcohol problems from the Rutgers Alcohol Problem Index at ages 24 and 34. Serial mediation and co‐twin comparison models were applied and included covariates from adolescence and early midlife. Results: There were weak direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction. However, there was stronger evidence for indirect effects, whereby young adult and early midlife alcohol problems serially mediated the relationship between adolescent alcohol misuse and early midlife somatic symptoms (β = 0.03, 95% CI [0.03, 0.04]), self‐rated health (β = −0.02, 95% CI [−0.03, −0.01]), and life satisfaction (β = −0.03, CI [−0.04, −0.02]). These serial mediation effects were robust in co‐twin comparison analyses. Conclusions: These results provide evidence that alcohol problems are a primary driver linking adolescent alcohol misuse and poor health outcomes across the lifespan. [ABSTRACT FROM AUTHOR]