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ObjectiveTo investigate the genetic architecture of internalizing symptoms in childhood and adolescence.MethodIn 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.ResultsThe meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.ConclusionGenetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Background and Aims: Electronic cigarette use has escalated rapidly in recent years, particularly among youth. Little is known about the genetic influences on e‐cigarette use. This study aimed to determine whether genetic risk for regular use of combustible cigarettes or for number of cigarettes smoked per day confers risk for ever e‐cigarette use or frequency of e‐cigarette use. Design, Setting, Participants, and Measurements: We used data from 9541 young adults from the Spit for Science longitudinal cohort study (2011–2019). Polygenic scores (PGS) of regular combustible cigarette use (PGS‐RCU) and cigarettes per day (PGS‐CPD) were constructed using summary statistics from the two largest available genome‐wide association study (GWAS) meta‐analysis of European ancestry and East Asian ancestry of combustible cigarette use and used to test whether the PGS of RCU or CPD predicted lifetime e‐cigarette use and frequency of past 30‐day e‐cigarette use in a diverse sample of young adults of African (AFR), Admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS) ancestry. Findings: The PGS‐RCU was associated with lifetime e‐cigarette use in the EUR sample (OR = 1.27, 95% CI = 1.19–1.36, P = 7.53 × 10−12), but not in the other subsamples (ps > 0.12). This association remained significant after excluding regular combustible cigarette smokers (OR = 1.21, 95% CI = 1.12–1.31, P = 3.36 × 10−6). There was no statistically significant association between PGS‐CPD and lifetime e‐cigarette use and neither the PGS‐RCU nor the PGS‐CPD were associated with frequency of e‐cigarette use in the past 30 days in any of the subsamples. Conclusions: Genetic factors associated with regular combustible cigarette use appear to be associated with ever e‐cigarette use in young adults. We did not find evidence for shared genetic factors influencing heaviness of use of combustible cigarettes and current e‐cigarette use frequency. [ABSTRACT FROM AUTHOR]