BackgroundHuman aggressive behavior (AGG) has a substantial genetic component. Here we present a large genome-wide association meta-analysis (GWAMA) of childhood AGG.MethodsWe analyzed assessments of AGG for a total of 328,935 observations from 87,485 children (aged 1.5 – 18 years), from multiple assessors, instruments, and ages, while accounting for sample overlap. We performed an overall analysis and meta-analyzed subsets of the data within rater, instrument, and age.ResultsHeritability based on the overall meta-analysis (AGGall) that could be attributed to Single Nucleotide Polymorphisms (SNPs) was 3.31% (SE=0.0038). No single SNP reached genome-wide significance, but 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 and in retrospectively assessed childhood aggression. We obtained moderate-to-strong genetic correlations (rg‘s) 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). Genetic correlations between AGG and psychiatric disorders were strongest for mother- and self-reported AGG.ConclusionsThe current GWAMA of childhood aggression provides a powerful tool to interrogate the genetic etiology of AGG by creating individual polygenic scores and genetic correlations with psychiatric traits.

Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355–0.578]), but inconsistent across tissues (correlation range [− 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses showed rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Gene-based analyses showed significant associations with three genes: WNT3 (p=1.13×10-06), CCL26 (p=1.88×10-06), and CENPO (p=2.54×10-06). Of these, WNT3 was previously associated with neuroticism, with which INToverall also shared a strong genetic correlation (rg=0.76). Genetic correlations were also observed with adult anxiety, depression, and the wellbeing 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. Overall, childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could explain both the persistence of internalising symptoms over time, and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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.

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified > 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N= 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences inh2Metabolite-hitsamong different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higherh2Metabolite-hitsestimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.

Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study (EWAS) of left-handedness. In a meta-analysis of 3,914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. We identified differentially methylated regions at 20q11.23 (P = 0.00004) and 2p25.1 (P = 0.03), which were less methylated in left-handed adults. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1,737), we observed moderately stable associations across age (correlation range [0.355–0.578]) but inconsistent across tissues (correlation range [-0.384-0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

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We report the first epigenome-wide association study of left-handedness, a trait with low heritability for which epigenetic mechanisms have been proposed as an underlying etiological mechanism. A region-based meta-analysis of whole blood genome-wide DNA methylation data from two cohorts (3,914 adults) identified differentially methylated regions annotated to BLCAP (20q11.23), a negative regulator of cell growth involved in apoptosis, NNAT (20q11.23), involved in brain development, and IAH1 (2p25.1), which encodes an acyl esterase. CpGs located in proximity to the SNPs from the largest GWAS of handedness were more strongly associated with left-handedness than other differentially methylated positions. In longitudinal whole blood samples, cord blood, and buccal cells from children (N = 1,967), the association with handedness displayed moderate stability across age, but little consistency across cell types. These findings suggest new candidate loci associated with handedness.