Genome-wide association study of antisocial personality disorder

Rautiainen, M-R; Paunio, Tiina; Repo-Tiihonen, Eila; Virkkunen, Matti; Ollila, Hanna; Sulkava, Sonja; Jolanki, Otto; Palotie, Aarno; Tiihonen, Jari

doi:10.1038/tp.2016.155

Cited by 88 publications

(51 citation statements)

References 55 publications

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“…We restricted lookup to associations with autosomal SNPs that were found in samples of European ancestry, resulting in three loci. One genome-wide significant hit was reported for adult antisocial personality disorder (rs4714329; OR=0.63 1 ; P =1.64E-09)[38]. The same SNP, however, had an opposite direction of effect in AGG overall (β=0.0022; P =0.41).…”

Section: Resultsmentioning

confidence: 99%

Genetic Association Study of Childhood Aggression across raters, instruments and age

Laan

Krapohl

et al. 2019

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

Genetic Association Study of Childhood Aggression across raters, instruments and age

Laan

Krapohl

et al. 2019

Preprint

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“…GWAS is believed to be an ideal approach for studying common genetic variations across the genome, given its key feature that no a priori hypotheses are established [22]. Indeed, GWAS of psychiatric disorders have led to the identification of multiple novel risk variants with known or unknown function relevant to the biology of illnesses [23-25], and substantial progress has been obtained toward understanding the genetic architecture and molecular pathogeneses (e.g., dendritic spine pathology) of these psychiatric disorders [26, 27]. Among the risk candidates discovered through SCZ and MDD GWAS studies [13-20], VRK2 (vaccinia-related kinase 2) is one of the few genes showing consistent genome-wide significant associations with both disorders.…”

Section: Introductionmentioning

confidence: 99%

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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“…In human, LRFN2 is associated with autism24, learning disabilities25, and antisocial personality disorder26. Lrfn2 overexpression promotes neurite outgrowth27, recruits NMDAR, and enhances the surface expression of transfected GluN2A (NR2A, a glutamate receptor subunit)23.…”

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confidence: 99%

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

et al. 2017

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Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state.

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Genome-wide association study of antisocial personality disorder

Cited by 88 publications

References 55 publications

Genetic Association Study of Childhood Aggression across raters, instruments and age

Genetic Association Study of Childhood Aggression across raters, instruments and age

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

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