A Bivariate Twin Study of Lifetime cannabis Initiation and Lifetime Regular Tobacco Smoking Across Three Different Countries.

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.

Adolescent leisure-time physical activity and eating disorders: a longitudinal population-based twin study.

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.

Cohort Effects on Tobacco Consumption and its Genetic and Environmental Variance Among Finnish Adults born between 1880-1957.

INTRODUCTION: Population research indicates that smoking behaviors in Finland have varied over time by sex and birth cohort. Smoking behaviors are influenced by genes and the environment; like the behaviors themselves, these underlying influences are not necessarily stable over time and may be modifiable by national drug policy. METHODS: We utilized longitudinal mixed effects models and causal-common-contingent twin models to evaluate sex and cohort effects on tobacco consumption and the underlying genetic and environmental variance components in a birth cohort sample of same-sex twins born in Finland between 1880-1957, assessed in 1975, 1981, 1990, and 2011. RESULTS: We identified significant main effects of age, sex, and cohort on quantity of cigarette consumption, as well as significant age×cohort and sex×cohort interactions. We also identified sex and cohort effects on the liability to initiate regular smoking and the magnitude of variation underlying quantity of cigarette consumption. That said, heritability and environmental contributions to both traits were not different between the four sex×cohort groups. CONCLUSIONS: Our results indicate sex and cohort effects on the prevalence of smoking and its underlying variation. Our results on changing prevalence mirror existing population-level research in Finnish samples, but we did not identify differences in heritability found in other studies of cohort effects in tobacco use, potentially due to power issues. These results highlight the importance of considering age, cohort, and timing of policy changes when evaluating changes in substance consumption across time. IMPLICATIONS: This study identifies sex and cohort effects influencing tobacco consumption in a sample of Finnish adult twins born between 1880-1957. Our results are in line with other population level research in Finland and research on cohort effects influencing alcohol use in the same sample. Our results highlight the intertwining effects of age, cohort, sex, and substance policies on substance use.

Longitudinal leisure-time physical activity profiles throughout adulthood and related characteristics: a 36-year follow-up study of the older Finnish Twin Cohort.

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.

Loci on chromosome 20 interact with rs16969968 to influence cigarettes per day in European ancestry individuals.

BACKGROUND: The understanding of the molecular genetic contributions to smoking is largely limited to the additive effects of individual single nucleotide polymorphisms (SNPs), but the underlying genetic risk is likely to also include dominance, epistatic, and gene-environment interactions. METHODS: To begin to address this complexity, we attempted to identify genetic interactions between rs16969968, the most replicated SNP associated with smoking quantity, and all SNPs and genes across the genome. RESULTS: Using the UK Biobank European subsample, we found one SNP, rs1892967, and two genes, PCNA and TMEM230, that showed a significant genome-wide interaction with rs16969968 for log10 CPD and raw CPD, respectively, in a sample of 116 442 individuals who self-reported currently or previously smoking. We extended these analyses to individuals of South Asian descent and meta-analyzed the combined sample of 117 212 individuals of European and South Asian ancestry. We replicated the gene findings in a meta-analysis of five Finnish samples (N=40 140): FinHealth, FINRISK, Finnish Twin Cohort, GeneRISK, and Health-2000-2011. CONCLUSIONS: To our knowledge, this represents the first reliable epistatic association between single nucleotide polymorphisms for smoking behaviors and provides a novel direction for possible future functional studies related to this interaction. Furthermore, this work demonstrates the feasibility of these analyses by pooling multiple datasets across various ancestries, which may be applied to other top SNPs for smoking and/or other phenotypes.

Metabolic syndrome and epigenetic aging: a twin study.

BACKGROUND: Metabolic syndrome (MetS) is associated with premature aging, but whether this association is driven by genetic or lifestyle factors remains unclear. METHODS: Two independent discovery cohorts, consisting of twins and unrelated individuals, were examined (N = 268, aged 23-69 years). The findings were replicated in two cohorts from the same base population. One consisted of unrelated individuals (N = 1 564), and the other of twins (N = 293). Participants' epigenetic age, estimated using blood DNA methylation data, was determined using the epigenetic clocks GrimAge and DunedinPACE. The individual-level linear regression models for investigating the associations of MetS and its components with epigenetic aging were followed by within-twin-pair analyses using fixed-effects regression models to account for genetic factors. RESULTS: In individual-level analyses, GrimAge age acceleration was higher among participants with MetS (N = 56) compared to participants without MetS (N = 212) (mean 2.078 [95% CI = 0.996,3.160] years vs. -0.549 [-1.053,-0.045] years, between-group p = 3.5E-5). Likewise, the DunedinPACE estimate was higher among the participants with MetS compared to the participants without MetS (1.032 [1.002,1.063] years/calendar year vs. 0.911 [0.896,0.927] years/calendar year, p = 4.8E-11). An adverse profile in terms of specific MetS components was associated with accelerated aging. However, adjustments for lifestyle attenuated these associations; nevertheless, for DunedinPACE, they remained statistically significant. The within-twin-pair analyses suggested that genetics explains these associations fully for GrimAge and partly for DunedinPACE. The replication analyses provided additional evidence that the association between MetS components and accelerated aging is independent of the lifestyle factors considered in this study, however, suggesting that genetics is a significant confounder in this association. CONCLUSIONS: The results of this study suggests that MetS is associated with accelerated epigenetic aging, independent of physical activity, smoking or alcohol consumption, and that the association may be explained by genetics.

Dementia risk factors in former contact sports participants: prospective cohort study.

Background: The elevated dementia incidence in retired contact sport participants might be explained by a higher prevalence of established risk factors for the disease relative to the general population. Methods: In this cohort study, former elite participants active between 1920 and 1965 in soccer (N=303), boxing (N=281), and wrestling (N=318) were recruited using sports yearbooks and records of sports associations. Men in a population control group were identified using records from a compulsory medical examination (N=1712). All study members were linked to hospital registers (1970-2015) and self-completion questionnaires were circulated (1985, 1995) from which we captured data on nine established risk factors for dementia: hypertension and diabetes status, alcohol intake, loneliness, depressive symptoms, cigarette smoking, body weight, educational attainment, and physical activity. Results: There was little suggestion that former participants in contact sports had a higher prevalence of dementia risk factors relative to the general population. Rather, the balance of evidence was for more favourable risk factor levels in former athletes, as was particularly evident for ever having smoked cigarettes (range in odds ratios [95% confidence interval]: 0.32 [0.21, 0.48] for wrestling to 0.52 [0.36, 0.75] for soccer) and leisure-time physical activity (range in beta coefficients [95% confidence interval]: 1.34 [0.66, 2.02] for soccer to 1.80 [1.07, 2.52] for boxing). Conclusions: The increased dementia rates in retired contact sport participants evident in epidemiological studies is unlikely to be explained by the risk factors examined here. This implicates other characteristics of contact sports, including a history of repeated head impact.

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

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

Bone marrow metabolism is affected by body weight and response to exercise training varies according to anatomical location.

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 18 F-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.

Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use.

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9436 participants (7795 European and 1641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 [Formula: see text]: cg22572071 near gene ADGRF1, cg15280358 in ADAM12, cg00813162 in ACTN1, and cg01101459 near LINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.

DNA methylation sites in early adulthood characterised by pubertal timing and development: a twin study.

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.

Chronotype and mortality - a 37-year follow-up study in Finnish adults.

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.

Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study.

BACKGROUND: Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. METHODS: Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140 000 individuals. RESULTS: Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. CONCLUSIONS: These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.

The association between night shift work and breast cancer risk in the Finnish twins cohort.

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.

Perceived Occupational Noise Exposure and Depression in Young Finnish Adults.

We investigated the association between perceived occupational noise exposure and depressive symptoms in young Finnish adults and whether noise sensitivity moderates this association. This study was based on an ongoing longitudinal twin study. We included those who had been working daily (n = 521) or weekly (n = 245) during the past 12 months (mean age 22.4, SD 0.7, 53% female). We asked about occupational noise exposure at age 22 and assessed depressive symptoms using the General Behavior Inventory (GBI) at age 17 and 22. Noise sensitivity and covariates were used in linear regression models. Perceived daily occupational noise exposure was associated, as a statistically independent main effect with depressive symptoms at age 22 (beta 1.19; 95% CI 0.09, 2.29) among all, and separately for females (beta 2.22; 95% CI 0.34, 4.09) but not males (beta 0.22; 95% CI -1.08, 1.52). Noise sensitivity was independently associated with depressive symptoms among all (beta 1.35; 95% CI 0.54, 2.17), and separately for males (beta 1.96; 95% CI 0.68, 3.24) but not females (beta 1.05; 95 % CI -0.04, 2.13). Noise sensitivity was independent of perceived occupational noise exposure. Pre-existing depressive symptoms at age 17 were predictive of perceived occupational noise exposure, suggesting complex interactions of noise and depression.

Mortality Associations With DNA Methylation-Based Biological Aging and Physical Functioning Measures Across a 20-Year Follow-up Period.

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.

Longitudinal association of childhood physical activity and physical fitness with physical activity in adolescence: insights from the IDEFICS/I.Family study.

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.

The role of adolescent lifestyle habits in biological aging: A prospective twin study.

Background: Adolescence is a stage of fast growth and development. Exposures during puberty can have long-term effects on health in later life. This study aims to investigate the role of adolescent lifestyle in biological aging. Methods: The study participants originated from the longitudinal FinnTwin12 study (n = 5114). Adolescent lifestyle-related factors, including body mass index (BMI), leisure-time physical activity, smoking, and alcohol use, were based on self-reports and measured at ages 12, 14, and 17 years. For a subsample, blood-based DNA methylation (DNAm) was used to assess biological aging with six epigenetic aging measures in young adulthood (21-25 years, n = 824). A latent class analysis was conducted to identify patterns of lifestyle behaviors in adolescence, and differences between the subgroups in later biological aging were studied. Genetic and environmental influences on biological aging shared with lifestyle behavior patterns were estimated using quantitative genetic modeling. Results: We identified five subgroups of participants with different adolescent lifestyle behavior patterns. When DNAm GrimAge, DunedinPoAm, and DunedinPACE estimators were used, the class with the unhealthiest lifestyle and the class of participants with high BMI were biologically older than the classes with healthier lifestyle habits. The differences in lifestyle-related factors were maintained into young adulthood. Most of the variation in biological aging shared with adolescent lifestyle was explained by common genetic factors. Conclusions: These findings suggest that an unhealthy lifestyle during pubertal years is associated with accelerated biological aging in young adulthood. Genetic pleiotropy may largely explain the observed associations. Funding: This work was supported by the Academy of Finland (213506, 265240, 263278, 312073 to J.K., 297908 to M.O. and 341750, 346509 to E.S.), EC FP5 GenomEUtwin (J.K.), National Institutes of Health/National Heart, Lung, and Blood Institute (grant HL104125), EC MC ITN Project EPITRAIN (J.K. and M.O.), the University of Helsinki Research Funds (M.O.), Sigrid Juselius Foundation (J.K. and M.O.), Yrjö Jahnsson Foundation (6868), Juho Vainio Foundation (E.S.) and Päivikki and Sakari Sohlberg foundation (E.S.).

For most animals, events that occur early in life can have a lasting impact on individuals' health. In humans, adolescence is a particularly vulnerable time when rapid growth and development collide with growing independence and experimentation. An unhealthy lifestyle during this period of rapid cell growth can contribute to later health problems like heart disease, lung disease, and premature death. This is due partly to accelerated biological aging, where the body deteriorates faster than what would be expected for an individual's chronological age. One way to track the effects of lifestyle on biological aging is by measuring epigenetic changes. Epigenetic changes consist on adding or removing chemical 'tags' on genes. These tags can switch the genes on or off without changing their sequences. Scientists can measure certain epigenetic changes by measuring the levels of methylated DNA ­ DNA with a chemical 'tag' known as a methyl group ­ in blood samples. Several algorithms ­ known as 'epigenetic clocks' ­ are available that estimate how fast an individual is aging biologically based on DNA methylation. Kankaanpää et al. show that unhealthy lifestyles during adolescence may lead to accelerated aging in early adulthood. For their analysis, Kankaanpää et al. used data on the levels of DNA methylation in blood samples from 824 twins between 21 and 25 years old. The twins were participants in the FinnTwin12 study and had completed a survey about their lifestyles at ages 12, 14, and 17. Kankaanpää et al. classified individuals into five groups depending on their lifestyles. The first three groups, which included most of the twins, contained individuals that led relatively healthy lives. The fourth group contained individuals with a higher body mass index based on their height and weight. Finally, the last group included individuals with unhealthy lifestyles who binge drank, smoked and did not exercise. After estimating the biological ages for all of the participants, Kankaanpää et al. found that both the individuals with higher body mass indices and those in the group with unhealthy lifestyles aged faster than those who reported healthier lifestyles. However, the results varied depending on which epigenetic clock Kankaanpää et al. used to measure biological aging: clocks that had been developed earlier showed fewer differences in aging between groups; while newer clocks consistently found that individuals in the higher body mass index and unhealthy groups were older. Kankaanpää et al. also showed that shared genetic factors explained both unhealthy lifestyles and accelerated biological aging. The experiments performed by Kankaanpää et al. provide new insights into the vital role of an individual's genetics in unhealthy lifestyles and cellular aging. These insights might help scientists identify at risk individuals early in life and try to prevent accelerated aging.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.