Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology

Retz, Wolfgang; Retz-Junginger, Petra; Supprian, Tillmann; Thome, Johannes; Rösler, Michael

doi:10.1002/bsl.589

Cited by 178 publications

(105 citation statements)

References 50 publications

(21 reference statements)

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“…Accordingly, 5HTT constitutes another candidate gene for violent behavior. A small, yet increasing number of studies also investigated the implications of 5HTT genotype on aggression and demonstrated an association between short 5HTT alleles and violent behavior (Gerra et al, 2004;Retz et al, 2004;Liao et al, 2004), although the latter study conveyed several problems as the polymorphism was not in Hardy-Weinberg equilibrium. Gene-environment interactions have not yet been examined in humans.…”

Section: Discussionmentioning

confidence: 99%

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

Reif

Rösler

Freitag

et al. 2007

Neuropsychopharmacol

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Aggressive behavior is influenced by variation in genes of the serotonergic circuitry and early-life experience alike. The present study aimed at investigating the contribution of polymorphisms shown to moderate transcription of two genes involved in serotonergic neurotransmission (serotonin transporter, 5HTT, and monoamine oxidase A, MAOA) to the development of violence and to test for gene-environment interactions relating to adverse childhood environment. A cohort of 184 adult male volunteers referred for forensic assessment participated in the study. Each individual was assigned to either a violent or a nonviolent group. Logistic regression was performed and the best-fitting model, with a predictive power of 74%, revealed independent effects of adverse childhood environment and MAOA genotype. High environmental adversity during childhood was associated significantly with violent behavior. Forty-five percent of violent, but only 30% of nonviolent individuals carried the low-activity, short MAOA allele. Most interestingly, an interaction effect between childhood environment and 5HTT genotype on violent behavior was found in that high adversity during childhood impacted only the later-life violence if the short promoter alleles were present. These findings indicate complex interactions between genetic variation of the serotonergic circuitry and environmental factors arguing against simplistic, mono-causal explanations of violent behavior.

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Section: Discussionmentioning

confidence: 99%

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

Reif

Rösler

Freitag

et al. 2007

Neuropsychopharmacol

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225

156

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“…[23][24][25] The relationship between impaired serotonergic function and aggression is well established. 26 One potential pathway by which the 5-HTTLPR gene is related to impulsivity and aggression is through observed alterations in amygdala function as the amygdala, along with the prefrontal cortex and orbital cortex, is thought to play a role in the emergence of violent behavior via faulty regulation of negative emotion.…”

Section: Serotonin Transportermentioning

confidence: 99%

Stress, Genes and the Biology of Suicidal Behavior

Currier

Mann

2008

Psychiatric Clinics of North America

131

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Suicidal behavior is in part heritable. Studies seeking the responsible candidate genes have examined genes involved in neurotransmitter systems demonstrated to have altered function in suicide and attempted suicide. These neurotransmitter systems include the serotonergic, noradrenergic and dopaminergic systems and the HPA axis. With some exceptions, most notably the serotonin transporter promotor HTTLPR polymorphism, replication of candidate gene association studies findings has proven difficult. This chapter reviews what is known of specific gene effects and geneenvironment interactions that influence risk for suicidal behavior. Effects of childhood stress on development and how that influences adult responses to current stress will be shown to be relevant for mood disorders, aggressive/impulsive traits and suicidal behavior. KeywordsSuicide; Mood Disorders; Genetics; Stress; Serotonin; HPA axis Suicidal Behavior and GeneticsFamily, twin, and adoption studies provide evidence of the heritability of suicide and attempted suicide, in part independent of the familial transmission of major psychiatric disorders (see Brent & Mann for a review 1 ). From twin studies, based on case and register studies, estimates of heritability for suicide range between 21-50%, and 30-55% for a broader phenotype of suicidal behavior (attempts, thoughts, plans) based on general population studies. 2 Identifying the relevant genes and the neurobiological pathways through which they contribute to the etiology of suicidal behavior is important for designing and implementing preventative strategies. The first wave of genetic studies sought to identify genes involved in suicide and/ or attempted suicide by linkage studies or specific single nucleotide polymorphisms (SNPs) in association studies. Emerging approaches aim to investigate functional genomics using microarray technologies to profile expression of thousands of genes simultaneously (see Mirnics et al 3 for a review) or doing a genome wide array for hundreds of thousands of SNPs.Candidate genes for association studies have been generally selected based on evidence from neurobiological studies in suicide. Consequently, the serotonergic system has been most extensively investigated, with other target systems including the dopaminergic and

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“…23 Since then, many more groups have examined this gene in other behavioural disorders including anxiety-related traits, suicide, bipolar mood disorder, attention deficit hyperactivity disorder, impulsive aggressive behaviour and psychoticism. [24][25][26][27][28][29] Unfortu- …”

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confidence: 99%

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

et al. 2005

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Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P ¼ 0.002, AH2 P ¼ 0.014), the test of semantic memory (P ¼ 0.010) and general cognitive ability (P ¼ 0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly. Keywords: serotonin transporter; polymorphism; cognition; memory; genes; associationIn an increasingly long-lived population severe cognitive impairment, caused by either the normal ageing process or dementia, is an escalating problem that currently has no effective treatment. Cognitive ability and its rate of decline are highly heritable and both have been shown to predict dementia onset. [1][2][3][4] Of the 13 quantitative trait loci (QTL) currently associated with the level of cognitive ability in normal individuals the most widely reported are located in genes involved in synaptic transmission. 5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning. 20,21 There is also a decrease in total brain serotonin with age that may predispose the elderly to depression, dementia and cognitive dysfunction. 22 Despite the importance of serotonin as a modulator of memory and learning the influence of two functional polymorphisms (HTTLPR and VNTR2) in the SLC6A4 gene, which codes for a protein responsible for the reuptake of serotonin, have n...

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Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology

Cited by 178 publications

References 50 publications

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

Stress, Genes and the Biology of Suicidal Behavior

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

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