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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.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank ( N  = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/ MAGI2-AS3 in hippocampus; rs1862416/ TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits ( r g  = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking. There is strong genetic evidence for cigarette smoking behaviors, yet little is known on nicotine dependence (ND). Here, the authors perform a genome-wide association study on ND in 58,000 smokers, identifying five genome-wide significant loci.

The causal impacts of recreational cannabis legalization are not well understood due to the number of potential confounds. We sought to quantify possible causal effects of recreational cannabis legalization on substance use, substance use disorder, and psychosocial functioning, and whether vulnerable individuals are more susceptible to the effects of cannabis legalization than others. We used a longitudinal, co-twin control design in 4043 twins ( = 240 pairs discordant on residence), first assessed in adolescence and now age 24-49, currently residing in states with different cannabis policies (40% resided in a recreationally legal state). We tested the effect of legalization on outcomes of interest and whether legalization interacts with established vulnerability factors (age, sex, or externalizing psychopathology). In the co-twin control design accounting for earlier cannabis frequency and alcohol use disorder (AUD) symptoms respectively, the twin living in a recreational state used cannabis on average more often ( = 0.11, = 1.3 × 10 ), and had fewer AUD symptoms ( = -0.11, = 6.7 × 10 ) than their co-twin living in an non-recreational state. Cannabis legalization was associated with no other adverse outcome in the co-twin design, including cannabis use disorder. No risk factor significantly interacted with legalization status to predict any outcome. Recreational legalization was associated with increased cannabis use and decreased AUD symptoms but was not associated with other maladaptations. These effects were maintained within twin pairs discordant for residence. Moreover, vulnerabilities to cannabis use were not exacerbated by the legal cannabis environment. Future research may investigate causal links between cannabis consumption and outcomes.

Externalizing psychopathology in early adolescence is a highly heritable risk factor for drug use, yet how it relates to marijuana use development is not well-characterized. We evaluate this issue in independent twin samples from Colorado (N = 2608) and Minnesota (N = 3630), assessed from adolescence to early adulthood. We used a biometric latent growth model of marijuana use frequency with data from up to five waves of assessment from ages 14 to 30, to examine change in marijuana use and its relationship with a factor model of adolescent externalizing psychopathology. The factor structure of adolescent externalizing psychopathology was similar across samples, as was the association between that common factor and early marijuana use (Minnesota r = 0.67 [0.60, 0.75]; Colorado r = 0.69 [0.59, 0.78]), and increase in use (Minnesota r = 0.18 [0.10, 0.26]; Colorado r = 0.20 [0.07, 0.34]). Early use was moderately heritable in both samples (Minnesota h2 = 0.57 [0.37, 0.79]; Colorado h2 = 0.42 [0.14, 0.73]). Increase in use was highly heritable in Minnesota (h2 = 0.82 [0.72, 0.88]), less so in Colorado (h2 = 0.22 [0.01, 0.66]), and shared environmental effects were larger in Colorado (c2 = 0.55 [0.14, 0.83]) than Minnesota (c2 = 0 [0, 0.06]). We found moderate genetic correlations between externalizing psychopathology and early use in both samples. Finally, additional analyses in the Minnesota sample indicated that marijuana use decreased during the late 20s. This decline is strongly heritable (h2 = 0.73 [0.49, 0.91]) and moderately negatively correlated with adolescent externalizing psychopathology (r = − 0.41 [− 0.54, − 0.28]). Adolescent externalizing psychopathology is genetically correlated with change in late adolescent marijuana use (late teens, early 20s), as well as maintenance of use in early adulthood (late 20 s) even after controlling for the effects of early use.

Reproducibility is recognized as essential to scientific progress and integrity. Replication studies and large-scale replication projects, aiming to quantify different aspects of reproducibility, have become more common. Since no standardized approach to measuring reproducibility exists, a diverse set of metrics has emerged and a comprehensive overview is needed. We conducted a scoping review to identify large-scale replication projects that used metrics and methodological papers that proposed or discussed metrics. The project list was compiled by the authors. For the methodological papers, we searched Scopus, MedLine, PsycINFO and EconLit. Records were screened in duplicate against pre-defined inclusion criteria. Demographic information on included records and information on reproducibility metrics used, suggested or discussed was extracted. We identified 49 large-scale projects and 97 methodological papers and extracted 50 metrics. The metrics were characterized based on type (formulas and/or statistical models, frameworks, graphical representations, studies and questionnaires, algorithms), input required and appropriate application scenarios. Each metric addresses a distinct question. Our review provides a comprehensive resource in the form of a ‘live’, interactive table for future replication teams and meta-researchers, offering support in how to select the most appropriate metrics that are aligned with research questions and project goals.

Sleep medication use is an indicator of underlying sleep problems that might be induced by various factors such as alcohol use. However, the longitudinal relationship between drinking and sleep problems remains poorly understood. We investigated associations between sleep medication and alcohol use throughout adulthood, and examined the role of familial and potential confounding factors contributing to these associations. We used information of zygosity and self-report questionnaire data over a follow-up period of 36 years from the Older Finnish Twin Cohort (N = 13 851). Logistic regression analyses suggested consistent associations between sleep medication use and heavy/binge drinking at all four time points (OR range = 1.36–3.18, P < 0.05), implying that increased drinking is associated with increased sleep medication use over time. Cross-lagged path analyses suggested that moderate/heavy and binge drinking predict sleep medication use at most time points (OR range = 1.15–1.94, P < 0.05), whilst sleep medication use predicts subsequent abstaining from alcohol (OR range = 2.26–2.47, P < 0.05). Within-pair analyses implied that familial factors play a role, and quantitative genetic modelling estimated genetic factors to explain approximately 80 % of the lifetime association of sleep medication use with moderate/heavy and binge drinking. Drinking is associated with sleep medication use throughout adulthood. Further, our results suggest that drinking is likely to predict sleep medication use, thereby potentially constituting a risk factor for sleep problems, and that genetic factors contribute to the association. These findings are important in terms of better understanding the development of sleep and alcohol use disorders. •We examined associations between alcohol and sleep medication use over 36 years in Finnish twins (N = 13 851).•Sleep medication use was associated with heavy and binge drinking at all time points.•Moderate, heavy and binge drinking predicted subsequent sleep medication use.•Sleep medication use predicted subsequent abstaining from alcohol.•Genetic factors play an important role in the associations.

The Lutheran Congregation at Brush Valley was one of the oldest in the Commonwealth of Pennsylvania, being founded in 1794 by a group of German pioneers. Very few records exist of the first two churches on the property. Extant records note that both were built in the existing graveyard, but the exact locations of the churches and the graves around them are not known. These uncertainties have made it difficult for the current Board of Directors of the cemetery to determine where space may be available for additional burials in the future. This thesis presents the results of ground-penetrating radar, electrical resistivity surveys, and ground truthing of a 40x40 meter area in the old section of the cemetery to the west of the current church building as they pertain to identifying the locations of the original churches, determining if any physical remains of the buildings are still present, and assessing the number of unmarked graves present within the area of survey.In total, 183 anomalies are interpreted as burials: 73 likely burials and 110 possible burials; of these, at least 38 are interpreted as child or infant burials. The location of the Old Log Church is interpreted to be associated with Anomaly 6 in Grid 1 and the location of the second church is interpreted to be associated with Anomaly 12 in Grid 3.

Alcohol, tobacco, and cannabis are three of the most commonly consumed substances in the United States. The development of substance use is influenced by genes, the familial environment, and unique environmental exposures. One such exposure is legal policy surrounding the purchase and consumption of these substances, and cannabis policies in particular are changing dramatically across the United States, raising concerns about the potential for public health consequences associated with substance use. In the present work, we focus on the development of substance use in a normative community sample, as well as perturbations to substance use development and substance related outcomes as a consequence of recreational legalization using causally informative genetic longitudinal designs. Study 1 explores normative developmental trends of cannabis use in recreationally illegal environments and its relationship to development of alcohol and tobacco consumption from adolescence through mid-adulthood. Study 1 also investigates the genetic and environmental influences underlying all three substances and influences unique to each substance over time. Study 2 evaluates the causal impact of recreational legalization on cannabis frequency with a co-twin control model, as well as the changes to the magnitude genetic and environmental influences on cannabis use in a longitudinal gene-environment interaction model. Study 3 expands on this to evaluate the impact of recreational legalization on a broad range of psychiatric and psychosocial outcomes associated with cannabis use, and further examines whether vulnerable individuals are at exacerbated risk for negative outcomes due to legalization. Together, these studies use rigorous designs to expand on the existing literature and provide evidence consistent with a causal impact of cannabis legalization on cannabis use. Furthermore, our results suggest that cannabis legalization may perturb normative adult decreases in substance intake, but this is not coupled with negative psychosocial outcomes in adulthood.

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.

Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. We replicated the well-known association at the locus (lead single-nucleotide polymorphism [SNP]: rs147144681,  = 1.27E-11 in EUR; lead SNP = rs2036527,  = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a \"problematic tobacco use\" factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs). Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.