Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology.

BACKGROUND: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. METHODS: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. RESULTS: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. CONCLUSIONS: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.

Direct and Indirect Genetic Effects on Aggression.

Background: Family members resemble each other in their propensity for aggression. In twin studies, approximately 50% of the variance in aggression can be explained by genetic influences. However, if there are genotype-environment correlation mechanisms, such as environmental manifestations of parental and sibling genotypes, genetic influences may partly reflect environmental influences. In this study, we investigated the importance of indirect polygenic score (PGS) effects on aggression. Methods: We modeled the effect of PGSs based on 3 genome-wide association studies: early-life aggression, educational attainment, and attention-deficit/hyperactivity disorder (ADHD). The associations with aggression were tested in a within- and between-family design (37,796 measures from 7740 individuals, ages 3-86 years [mean = 14.20 years, SE = 12.03], from 3107 families, 55% female) and in a transmitted/nontransmitted PGS design (42,649 measures from 6653 individuals, ages 3-61 years [mean = 11.81 years, SE = 8.68], from 3024 families, 55% female). All participants are enrolled in the Netherlands Twin Register. Results: We found no evidence for contributions of indirect PGS effects on aggression in either a within- and between-family design or a transmitted/nontransmitted PGS design. Results indicate significant direct effects on aggression for the PGSs based on early-life aggression, educational attainment, and ADHD, although explained variance was low (within- and between-family: early-life aggression R2 = 0.3%, early-life ADHD R2 = 0.6%, educational attainment R2 = 0.7%; transmitted/nontransmitted PGSs: early-life aggression R2 = 0.2%, early-life ADHD R2 = 0.9%, educational attainment R2 = 0.5%). Conclusions: PGSs included in the current study had a direct (but no indirect) effect on aggression, consistent with results of previous twin and family studies. Further research involving other PGSs for aggression and related phenotypes is needed to determine whether this conclusion generalizes to overall genetic influences on aggression.

Genetics and epigenetics of human aggression.

There is substantial variation between humans in aggressive behavior, with its biological etiology and molecular genetic basis mostly unknown. This review chapter offers an overview of genomic and omics studies revealing the genetic contribution to aggression and first insights into associations with epigenetic and other omics (e.g., metabolomics) profiles. We allowed for a broad phenotype definition including studies on "aggression," "aggressive behavior," or "aggression-related traits," "antisocial behavior," "conduct disorder," and "oppositional defiant disorder." Heritability estimates based on family and twin studies in children and adults of this broadly defined phenotype of aggression are around 50%, with relatively small fluctuations around this estimate. Next, we review the genome-wide association studies (GWAS) which search for associations with alleles and also allow for gene-based tests and epigenome-wide association studies (EWAS) which seek to identify associations with differently methylated regions across the genome. Both GWAS and EWAS allow for construction of Polygenic and DNA methylation scores at an individual level. Currently, these predict a small percentage of variance in aggression. We expect that increases in sample size will lead to additional discoveries in GWAS and EWAS, and that multiomics approaches will lead to a more comprehensive understanding of the molecular underpinnings of aggression.

Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course.

We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12-70 years, Australia: 16-73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a 'rolling weights' model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41-70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role later in life.

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 meta-analysis (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 [Formula: see text]: 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 [Formula: see text]: 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.

Genomics of human aggression: current state of genome-wide studies and an automated systematic review tool.

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition 'aggression' (or 'aggressive behaviour', or 'aggression-related traits') included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P ≤ 1.0E), including 10 significant associations (P ≤ 5.0E). Nominal associations (P ≤ 1E) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.