Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder.

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.

Integrative Multi-omics Analysis of Childhood Aggressive Behavior.

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

Handedness and 23 Early Life Characteristics in 37,495 Dutch Twins.

In studies of singletons, a range of early-life characteristics have been reported to be associated with handedness, but some of these associations have failed to replicate. We examined associations between 23 early life characteristics with handedness in a large sample of 37,495 5-year-old twins. We considered three definitions of handedness: left-handedness (LH), mixed-handedness (MH), and non-right-handedness (NRH). Our main aim was to test whether the associations with sex, birth weight, gestational age, and season of birth - as reported in singletons - replicate in twins, and to examine twin-specific variables, including zygosity, chorionicity, birth order, and intertwin delivery time. Compared to previously published data from adults born as singletons (7.23%), the prevalence of NRH was higher in both twins (16.19%) and their parents (15.09%). In the twins, LH and NRH were associated with parents' LH. Male sex and lower gestational age were associated with NRH, and LH was associated with not being breastfed. MH was related to neurodevelopmental delays and higher externalizing problems later in childhood. Other previously reported associations were not replicated, and no twin-specific characteristics were related to handedness. These results emphasize the importance of considering multiple definitions of handedness and indicate a small number of replicated associations across studies.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Genetic factors explain a significant part of associations between adolescent well-being and the social environment.

Socio-environmental factors play an important role in adolescent well-being, but potential genetic contributions to these associations are rarely assessed. To address this gap in the literature, associations between well-being and family conflict and functioning, number of friends, friendship importance and satisfaction, and leisure time variables were studied in N = ~ 4700 twin pairs from the Netherlands Twin Register, us ing generalized estimating equations and twin-difference scores. When twin-difference scores indicated a role for genetic factors, we used bivariate genetic models to quantify genetic and environmental contributions to these associations. We identify significant associations between well-being and family functioning, family conflict, different leisure time activities, number of friends, and satisfaction with friendships. Additionally, we find evidence for large (73-91%) genetic influence on the associations between well-being and family conflict and functioning, leisure time sport/scouting clubs, and satisfaction with friendships. Finally, findings support the hypothesis of a causal association between well-being and family conflict and functioning. These findings have important implications for research into the social correlates of well-being in adolescence, as not taking genetic factors into account leads to overestimations of the influence of identified correlates and consequently to recommendations of these correlates as intervention targets.

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (ß = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (ß = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.

Associations of sleep with psychological problems and well-being in adolescence: causality or common genetic predispositions?

BACKGROUND: Whereas short and problematic sleep are associated with psychological problems in adolescence, causality remains to be elucidated. This study therefore utilized the discordant monozygotic cotwin design and cross-lagged models to investigate how short and problematic sleep affect psychological functioning. METHODS: Adolescent twins (N = 12,803, 13-20 years, 42% male) completed questionnaires on sleep and psychological functioning repeatedly over a two-year interval. Monozygotic twin pairs were classified as concordant or discordant for sleep duration and trouble sleeping. Resulting subgroups were compared regarding internalizing problems, externalizing problems, and subjective well-being. RESULTS: Cross-sectional analyses indicated associations of worse psychological functioning with both short sleep and problematic sleep, and cross-lagged models indicate bidirectional associations. Longitudinal analyses showed that an increase in sleep problems experienced selectively by one individual of an identical twin pair was accompanied by an increase of 52% in internalizing problem scores and 25% in externalizing problem scores. These changes were significantly different from the within-subject changes in cotwins with unchanged sleep quality (respectively, 3% increase and 5% decrease). Psychological functioning did, however, not worsen with decreasing sleep duration. CONCLUSIONS: The findings suggest that sleep quality, rather than sleep duration, should be the primary target for prevention and intervention, with possible effect on psychological functioning in adolescents.

Triplets, birthweight, and handedness.

The mechanisms behind handedness formation in humans are still poorly understood. Very low birthweight is associated with higher odds of left-handedness, but whether this is due to low birthweight itself or premature birth is unknown. Handedness has also been linked to development, but the role of birthweight behind this association is unclear. Knowing that birthweight is lower in multiple births, triplets being about 1.5 kg lighter in comparison with singletons, and that multiples have a higher prevalence of left-handedness than singletons, we studied the association between birthweight and handedness in two large samples consisting exclusively of triplets from Japan (n = 1,305) and the Netherlands (n = 947). In both samples, left-handers had significantly lower birthweight (Japanese mean = 1,599 g [95% confidence interval (CI): 1,526-1,672 g]; Dutch mean = 1,794 g [95% CI: 1,709-1,879 g]) compared with right-handers (Japanese mean = 1,727 g [95% CI: 1,699-1,755 g]; Dutch mean = 1,903 g [95% CI: 1,867-1,938 g]). Within-family and between-family analyses both suggested that left-handedness is associated with lower birthweight, also when fully controlling for gestational age. Left-handers also had significantly delayed motor development and smaller infant head circumference compared with right-handers, but these associations diluted and became nonsignificant when controlling for birthweight. Our study in triplets provides evidence for the link between low birthweight and left-handedness. Our results also suggest that developmental differences between left- and right-handers are due to a shared etiology associated with low birthweight.

Content, diagnostic, correlational, and genetic similarities between common measures of childhood aggressive behaviors and related psychiatric traits.

BACKGROUND: Given the role of childhood aggressive behavior (AGG) in everyday child development, precise and accurate measurement is critical in clinical practice and research. This study aims to quantify agreement among widely used measures of childhood AGG regarding item content, clinical concordance, correlation, and underlying genetic construct. METHODS: We analyzed data from 1254 Dutch twin pairs (age 8-10 years, 51.1% boys) from a general population sample for whom both parents completed the A-TAC, CBCL, and SDQ at the same occasion. RESULTS: There was substantial variation in item content among AGG measures, ranging from .00 (i.e., mutually exclusive) to .50 (moderate agreement). Clinical concordance (i.e., do the same children score above a clinical threshold among AGG measures) was very weak to moderate with estimates ranging between .01 and .43 for mother-reports and between .12 and .42 for father-reports. Correlations among scales were weak to strong, ranging from .32 to .70 for mother-reports and from .32 to .64 for father-reports. We found weak to very strong genetic correlations among the measures, with estimates between .65 and .84 for mother-reports and between .30 and .87 for father-reports. CONCLUSIONS: Our results demonstrated that degree of agreement between measures of AGG depends on the type (i.e., item content, clinical concordance, correlation, genetic correlation) of agreement considered. Because agreement was higher for correlations compared to clinical concordance (i.e., above or below a clinical cutoff), we propose the use of continuous scores to assess AGG, especially for combining data with different measures. Although item content can be different and agreement among observed measures may not be high, the genetic correlations indicate that the underlying genetic liability for childhood AGG is consistent across measures.

Harmonizing behavioral outcomes across studies, raters, and countries: application to the genetic analysis of aggression in the ACTION Consortium.

BACKGROUND: Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school-aged children to jointly analyze data from five large twin cohorts. METHODS: Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model-based phenotype harmonization approach. A bi-factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite-sex twins. RESULTS: The best-fitting model found a high level of overall heritability of aggression (~60%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of ~64% and ~58% in girls. Sibling interaction effects were only significant in the opposite-sex twin pairs: the interaction effect of males on their female co-twin differed from the effect of females on their male co-twin. An aggressive female had a positive effect on male co-twin aggression, whereas more aggression in males had a negative influence on a female co-twin. CONCLUSIONS: Opposite-sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.

Parental Age and Offspring Childhood Mental Health: A Multi-Cohort, Population-Based Investigation.

To examine the contributions of maternal and paternal age on offspring externalizing and internalizing problems, this study analyzed problem behaviors at age 10-12 years from four Dutch population-based cohorts (N = 32,892) by a multiple informant design. Bayesian evidence synthesis was used to combine results across cohorts with 50% of the data analyzed for discovery and 50% for confirmation. There was evidence of a robust negative linear relation between parental age and externalizing problems as reported by parents. In teacher-reports, this relation was largely explained by parental socio-economic status. Parental age had limited to no association with internalizing problems. Thus, in this large population-based study, either a beneficial or no effect of advanced parenthood on child problem behavior was observed.

Genetic and Environmental Influences on Different Forms of Bullying Perpetration, Bullying Victimization, and Their Co-occurrence.

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was ~ 70% for perpetration and ~ 65% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (~ 71%) and especially physical (~ 77%) and mostly by environmental factors for relational perpetration and victimization (~ 60%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

Association Between rs1051730 and Smoking During Pregnancy in Dutch Women.

INTRODUCTION: The common genetic variant (rs1051730) in the 15q24 nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 was associated with smoking quantity and has been reported to be associated also with reduced ability to quit smoking in pregnant women but results were inconsistent in nonpregnant women. The aim of this study was to explore the association between rs1051730 and smoking cessation during pregnancy in a sample of Dutch women. METHODS: Data on smoking during pregnancy were available from 1337 women, who ever smoked, registered at the Netherlands Twin Register (NTR). Logistic regression was used to assess evidence for the association of rs1051730 genotype on smoking during pregnancy. In a subsample of 561 women, we investigated the influence of partner's smoking. Educational attainment and year of birth were used as covariates in both analyses. RESULTS: There was evidence for a significant association between having one or more T alleles of the rs1051730 polymorphism and the likelihood of smoking during pregnancy (p = .03, odds ratio = 1.28, 95% CI = 1.02 to 1.61). However, this association attenuated when adjusting for birth cohort and educational attainment (p = .37, odds ratio = 1.12, 95% CI = 0.87 to 1.43). In the subsample, smoking spouse was highly associated with smoking during pregnancy, even when educational attainment and birth cohort were included in the model. CONCLUSIONS: Our results did not support a strong association between this genetic variant and smoking during pregnancy. However, a strong association was observed with the smoking behavior of the partner, regardless of the genotype of the women. IMPLICATIONS: The present study emphasizes the importance of social influences like spousal smoking on the smoking behavior of pregnant women. Further research is needed to address the role of rs1051730 genetic variant in influencing smoking cessation and the interaction with important environmental factors like the smoking behavior of the partner.

Pre- and Perinatal Characteristics Associated with Apgar Scores in a Review and in a New Study of Dutch Twins.

A literature review was carried out to identify pre and perinatal characteristics associated with variation in Apgar scores in population-based studies. The parameters identified in the literature search were included in the classical twin design study to estimate effects of pre and perinatal factors shared and nonshared by twins and to test for a contribution of genetic factors in 1- and 5-min Apgar scores in a large sample of Dutch monozygotic (MZ) and dizygotic (DZ) twins. The sample included MZ and DZ twins (N = 5181 pairs) recruited by the Netherlands Twin Register shortly after birth, with data on prenatal characteristics and Apgar scores at first and/or fifth minutes. The ordinal regression and structural equation modeling were used to analyze the effects of characteristics identified in the literature review and to estimate genetic and nongenetic variance components. The literature review identified 63 papers. Consistent with the review, we observed statistically significant effects of birth order, zygosity and gestational age (GA) for 1- and 5-min Apgar scores of both twins. Apgar scores are higher in first-born versus second-born twins and DZ first-born versus MZ first-born twins. Birth weight had an effect on the 5-min Apgar of the first born. Fetal presentation and mode of delivery had different effects on Apgar scores of first- and second-born twins. Parental characteristics and chorionicity did not have significant main effects on Apgar scores. The MZ twins' Apgar correlations equaled the DZ Apgar correlations. Our analyses suggest that individual differences in 1- and 5-min Apgar scores are attributable to shared and nonshared pre and perinatal factors, but not to genotypic factors of the newborns. The main predictors of Apgar scores are birth order, zygosity, GA, birth weight, mode of delivery and fetal presentation.

The Netherlands Twin Register: Longitudinal Research Based on Twin and Twin-Family Designs.

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity.

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1-3.75 Hz, theta 4-7.75 Hz, alpha 8-12.75 Hz, and beta 13-30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2-a known genetic marker for alcohol use disorder and epilepsy-significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q < .05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex-genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

Genetic and Environmental Influences on Self-Control: Assessing Self-Control with the ASEBA Self-Control Scale.

This study used a theoretically-derived set of items of the Achenbach System of Empirically Based Assessment to develop the Achenbach Self-Control Scale (ASCS) for 7-16 year olds. Using a large dataset of over 20,000 children, who are enrolled in the Netherlands Twin Register, we demonstrated the psychometric properties of the ASCS for parent-, self- and teacher-report by examining internal and criterion validity, and inter-rater and test-retest reliability. We found associations between the ASCS and measures of well-being, educational achievement, and substance use. Next, we applied the classical twin design to estimate the genetic and environmental contributions to self-control. Genetic influences accounted for 64-75% of the variance in self-control based on parent- and teacher-report (age 7-12), and for 47-49% of the variance in self-control based on self-report (age 12-16), with the remaining variance accounted by non-shared environmental influences. In conclusion, we developed a validated and accessible self-control scale, and show that genetic influences explain a majority of the individual differences in self-control across youth aged 7-16 years.

Why do children read more? The influence of reading ability on voluntary reading practices.

BACKGROUND: This study investigates the causal relationships between reading and print exposure and investigates whether the amount children read outside school determines how well they read, or vice versa. Previous findings from behavioural studies suggest that reading predicts print exposure. Here, we use twin-data and apply the behaviour-genetic approach of direction of causality modelling, suggested by Heath et al. (), to investigate the causal relationships between these two traits. METHOD: Partial data were available for a large sample of twin children (N = 11,559) and 262 siblings, all enrolled in the Netherlands Twin Register. Children were assessed around 7.5 years of age. Mothers completed questionnaires reporting children's time spent on reading activities and reading ability. Additional information on reading ability was available through teacher ratings and performance on national reading tests. For siblings reading test, results were available. RESULTS: The reading ability of the twins was comparable to that of the siblings and national norms, showing that twin findings can be generalized to the population. A measurement model was specified with two latent variables, Reading Ability and Print Exposure, which correlated .41. Heritability analyses showed that Reading Ability was highly heritable, while genetic and environmental influences were equally important for Print Exposure. We exploited the fact that the two constructs differ in genetic architecture and fitted direction of causality models. The results supported a causal relationship running from Reading Ability to Print Exposure. CONCLUSIONS: How much and how well children read are moderately correlated. Individual differences in print exposure are less heritable than individual differences in reading ability. Importantly, the present results suggest that it is the children's reading ability that determines how much they choose to read, rather than vice versa.

Genetic and environmental influences on conduct and antisocial personality problems in childhood, adolescence, and adulthood.

Conduct problems in children and adolescents can predict antisocial personality disorder and related problems, such as crime and conviction. We sought an explanation for such predictions by performing a genetic longitudinal analysis. We estimated the effects of genetic, shared environmental, and unique environmental factors on variation in conduct problems measured at childhood and adolescence and antisocial personality problems measured at adulthood and on the covariation across ages. We also tested whether these estimates differed by sex. Longitudinal data were collected in the Netherlands Twin Register over a period of 27 years. Age appropriate and comparable measures of conduct and antisocial personality problems, assessed with the Achenbach System of Empirically Based Assessment, were available for 9783 9-10-year-old, 6839 13-18-year-old, and 7909 19-65-year-old twin pairs, respectively; 5114 twins have two or more assessments. At all ages, men scored higher than women. There were no sex differences in the estimates of the genetic and environmental influences. During childhood, genetic and environmental factors shared by children in families explained 43 and 44% of the variance of conduct problems, with the remaining variance due to unique environment. During adolescence and adulthood, genetic and unique environmental factors equally explained the variation. Longitudinal correlations across age varied between 0.20 and 0.38 and were mainly due to stable genetic factors. We conclude that shared environment is mainly of importance during childhood, while genetic factors contribute to variation in conduct and antisocial personality problems at all ages, and also underlie its stability over age.

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.