Branched-chain amino acids linked to depression in young adults

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 branched-chain 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.Peer reviewe

Early adolescent aggression predicts antisocial personality disorder in young adults : a population-based study

Modestly prevalent in the general population (4%), but highly prevalent in prison populations (>40%), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population-based longitudinal twin cohort study with psychiatric interviews available at age 22 (N=1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants' aggression ratings were significant (pPeer reviewe

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

Teacher-rated aggression and co-occurring behaviors and emotional problems among schoolchildren in four population-based European cohorts

Aggressive behavior in school is an ongoing concern. The current focus is on specific manifestations such as bullying, but the behavior is broad and heterogenous. Children spend a substantial amount of time in school, but their behaviors in the school setting tend to be less well characterized than at home. Because aggression may index multiple behavioral problems, we used three validated instruments to assess means, correlations and gender differences of teacher-rated aggressive behavior with co-occurring externalizing/internalizing problems and social behavior in 39,936 schoolchildren aged 7-14 from 4 population-based cohorts from Finland, the Netherlands, and the UK. Correlations of aggressive behavior were high with all other externalizing problems (r: 0.47-0.80) and lower with internalizing problems (r: 0.02-0.39). A negative association was observed with prosocial behavior (r: -0.33 to -0.54). Mean levels of aggressive behavior differed significantly by gender. Despite the higher mean levels of aggressive behavior in boys, the correlations were notably similar for boys and girls (e.g., aggressive-hyperactivity correlations: 0.51-0.75 boys, 0.47-0.70 girls) and did not vary greatly with respect to age, instrument or cohort. Thus, teacher-rated aggressive behavior rarely occurs in isolation; boys and girls with problems of aggressive behavior likely require help with other behavioral and emotional problems. Important to note, higher aggressive behavior is not only associated with higher amounts of other externalizing and internalizing problems but also with lower levels of prosocial behavior.Peer reviewe

Childhood aggression and the co-occurrence of behavioural and emotional problems

Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychop

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 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. Results: The 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%, n(effective) = 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 (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic 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.Peer reviewe

Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p

Self-regulation of socioemotional behavior in twin adolescents: structural validation of a multidimensional inventory

Instruments for rating socioemotional behavior with a strong theoretical basis, broad coverage of behaviors, and that are well-validated are rare. Here, the Multidimensional Peer Nomination Inventory (MPNI) Form SERI (Socio(E]motional Regulation Inventory) was employed in a longitudinal population-based sample of Finnish twins (FinnTwin 12) at age 17 to study: (1) the structure of self-ratings on self-regulation of socioemotional behavior, (2) concurrent, discriminative, and predictive validity of the scales, and (3) genetic and environmental factors contributing to individual differences in self-regulation. A bipolar factor for self-regulation was interpreted as representing p-factor (general psychopathology) versus src-factor (self-regulation capacity). Each was further categorized into a Problem behavior scale that comprised Hyperactivity/Inattention, Aggression, and Anxiety subscales, and a Prosocial behavior scale. These scales had high correlations with co-twin ratings at age 17 and similarly formed scales for self- and co-twin ratings at age 14, and good discriminative validity with items for social position and resilience. Modeling the twin data indicated that the p-factor and src-factor are moderately heritable and are influenced by both genetic and unique environmental factors. The inventory can be used for self- and sibling ratings in a population study

Genome-wide analyses of vocabulary size in infancy and toddlerhood:associations with ADHD, literacy and cognition-related traits

BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).MethodsWe studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h2) and genetic correlations (rg), and modelled underlying factor structures with multivariate models.ResultsEarly-life vocabulary size was modestly heritable (SNP-h2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (rg=0.69(SE=0.14) and rg=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: rg=0.58(SE=0.20) and rg=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: rg=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (rg=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (rg=-0.74(SE=0.23)), highlighting developmental heterogeneity.ConclusionsThe genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits