Age at Separation of Twin Pairs in the FinnTwin12 Study

Living in the same household exposes family members to shared environments and may be reflected in estimates of shared environment in twin analyses. The age at the separation of cotwins in a twin pair marks the end of such shared exposure, and the age of separation is commonly self-reported in studies. The objective of the study was to summarize the age at separation from residential records and use it to validate with self-reported separation status and age at the third and fourth wave of data collection in the FinnTwin12 cohort. Age at separation was generated from the address information, linking it to the Finnish Population information system since birth. Descriptive statistics by sex and zygosity are presented. The mean age at separation from residential records was 20.36 years old. Women separated earlier than men and dizygotic pairs earlier than monozygotic pairs. We also calculated the sensitivity and specificity with the self-reported separation status at waves 3 and 4, and interrater reliability with the self-reported separation age at wave 4. Age at separation from residential records had a relatively poor agreement with the self-report. This work enables us to use a more precise and objective measure for the shared environment in future twin studies.Peer reviewe

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

FinnTwin12 Cohort : An Updated Review

This review offers an update on research conducted with FinnTwin12 (FT12), the youngest of the three Finnish Twin Cohorts. FT12 was designed as a two-stage study. In the first stage, we conducted multiwave questionnaire research enrolling all eligible twins born in Finland during 1983–1987 along with their biological parents. In stage 2, we intensively studied a subset of these twins with in-school assessments at age 12 and semistructured poly-diagnostic interviews at age 14. At baseline, parents of intensively studied twins were administered the adult version of the interview. Laboratory studies with repeat interviews, neuropsychological tests, and collection of DNA were made of intensively studied twins during follow-up in early adulthood. The basic aim of the FT12 study design was to obtain information on individual, familial and school/neighborhood risks for substance use/abuse prior to the onset of regular tobacco and alcohol use and then track trajectories of use and abuse and their consequences into adulthood. But the longitudinal assessments were not narrowly limited to this basic aim, and with multiwave, multirater assessments from ages 11 to 12, the study has created a richly informative data set for analyses of gene–environment interactions of both candidate genes and genomewide measures with measured risk-relevant environments. Because 25 years have elapsed since the start of the study, we are planning a fifth-wave follow-up assessment.Peer reviewe

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

Associations with childhood aggressive behavior using multiple raters : co-occurrence, antisocial personality disorder prediction, and biomarkers

Problems of aggressive behavior affect as many as one in every six children and are associated with negative outcomes for not only the individual themselves, but also their family, friends, and community. Aggressive behavior includes a variety of different behaviors (e.g., yelling, hitting, bullying) and has been notoriously difficult to treat. In assessing aggression, researchers and clinicians have repeatedly been recommended to utilize reports from multiple informants (e.g., parents, teachers, the child him/herself) in order to obtain the most complete picture of the problem. In studying aggressive behavior, early research was initially focused on males only and severe outcomes, but now investigates gender similarities and differences and a broad range of behaviors related to aggression. While much has been learned from research thus far, new biological mechanisms and detailed phenotypic information are still important to continue clarifying the heterogenous nature of aggression and to improve ideas for personalized treatment. Thus, this thesis aimed to contribute to those efforts. Study I and II showed that aggressive behavior (as rated by all raters) often co-occurred with other externalizing behaviors and low prosocial behavior, and also co-occurred with internalizing problems but not as often. Patterns were similar across cohorts and genders, however, parents indicated more co-occurrence with internalizing problems and less co-occurrence with other externalizing behaviors than teachers did. Study III showed teacher and self ratings were able to predict ASPD, both in separate models and when both ratings were in the same model. Additionally, the direct aggression subtype (e.g., hitting, yelling) was able to predict ASPD well, for both genders. Furthermore, when the co-occurring influence of hyperactivity was removed from the aggression ratings (using a residual aggression variable with hyperactivity co-occurrence removed), aggressive behavior was still able to predict ASPD. Study IV showed the ketone body 3-hydroxybutyrate to be negatively associated with aggressive behavior in initial analyses. In more detailed modeling, nearly all raters of aggression showed the same trend with 3-hydroxybutyrate, including in fully adjusted models. In a model including both teacher and self ratings, 3-hydroxybutyrate was significantly associated with both aggressive behavior ratings. A replication dataset of young adult Dutch twins (N=960) showed support for the association found in FinnTwin12, however, the issue of whether there are gender differences of the association of 3-hydroxybutyrate with aggressive behavior remains to be clarified by future research. These findings help to clarify the co-occurrence of aggressive behavior with other behaviors across raters and countries, to show how common the co-occurrence is and that it should be taken into consideration when studying aggressive behavior, including from (epi)genetic or biological perspectives. Additionally, aggressive behavior, in particular direct aggression, can inform future ASPD risk, and obtaining behavior data from teachers and the child are of high importance. Furthermore, the new association of 3-hydroxybutyrate with aggressive behavior suggests new biological pathways to investigate to improve our understanding of aggressive behavior, including potential treatments. This thesis provides refinements to the aggressive behavior phenotype, new avenues for aggression biology investigations, and ideas for where to improve or personalize treatment options.Aggressiiviseen käyttäytymiseen liittyvät ongelmat vaikuttavat jopa joka kuudenteen lapseen, ja niihin liittyy kielteisiä seurauksia niin henkilölle itselleen kuin myös hänen läheisilleen. Aggressiivinen käyttäytyminen käsittää monenlaista ilmenemismuotoja (esim. huutaminen, lyöminen), ja sitä on tunnetusti vaikea hoitaa. Usein suositellaan, että aggressiivisuuden arvioinnissa kerättäisiin tietoa useista eri lähteistä (esim. vanhemmilta ja opettajilta), jotta ongelmasta saataisiin mahdollisimman kattava kuva. Alkuvaiheessa aggressiivisen käyttäytymisen tutkimuksessa keskityttiin lähinnä miehiin ja vaikeisiin aggressiivisen käytöksen ilmenemismuotoihin. Nykypäivänä tutkitaan myös sukupuolten välisiä yhtäläisyyksiä tai eroja, ja aggressiivisuuteen liittyvä käyttäytyminen ymmärretään laajempana jatkumona. Vaikka tähänastisesta tutkimuksesta on kertynyt paljon tietämystä, on edelleen tärkeää tutkia uusia biologisia mekanismeja ja erilaisia fenotyyppejä aggression esiintymismuotoja/ilmiasuja heterogeenisen luonteen selvittämiseksi ja uudenlaisten yksilöllisten hoitomuotojen kehittämiseksi. Tämän väitöskirjan tavoitteena oli tuottaa lisätietoa näistä aiheista. Tässä väitöskirjassa kuvaillaan yksityiskohtaisemmin aggressiivisen käyttäytymisen fenotyyppiä, esitellään uusia lähestymistapoja aggression biologisiin tutkimuksiin sekä tarjotaan uusia näkökulmia hoitovaihtoehtojen kehittämiseen ja yksilöllistämiseen. Tulokset selvensivät aggressiivisen käyttäytymisen ja muiden käyttäytymismuotojen välistä yhteyttä eri arvioijien raportoimana sekä eri maissa. Tulokset osoittavat, kuinka yleistä niiden samanaikainen esiintyminen on, ja että se olisi otettava huomioon. Aggressiivinen käyttäytyminen, erityisesti suora aggressio, voi myös kertoa kehittymässä olevan epäsosiaalisen persoonallisuushäiriön riskistä, ja on hyvin tärkeää hankkia käyttäytymistä koskevaa tietoa sekä opettajilta että lapselta itseltään. Lisäksi uusi löydös 3-hydroksivoihapon yhteydestä aggressiiviseen käyttäytymiseen viittaa uusiin biologisiin mekanismeihin. Niitä on tutkittava tarkemmin, jotta voimme ymmärtää aggressiivisesta käyttäytymistä paremmin ja kehittää häiritsevän aggressiivisen käyttäytymisen hoitoja