Anger management: Dopamine Receptor Allele and Nuclear Receptor Genes Are Associated with Anger and Aggression

Everyone knows someone whose “default” emotion is anger. They are like a one-trick pony, they are sad, so they express anger. They are scared, so they act angry. They are frustrated, so they are angry. When in children, it is painful to watch. When in adults, it is scary.

“Never rage against your coworkers, that’s what your family is for”

World’s Most Dysfunctional Inspirational Poster “Anger Management: Don’t Rage At Your Coworkers, That’s What Your Family Is For.

This has always been puzzling to me: why do these people get angry so much? Is it enjoyable to them, like blowing off a little neurotransmitter steam? And, since “tantrums” are a symptom of many other conditions, such as the low frustrational tolerance associated (sometimes) with autism or aspergers, I wondered if people who have temper tantrums have a particular type of autism.

So here are some new reports of genes associated with aggressive behavior: one is a dopamine receptor, and one relates to brain cell growth in embryos. There’s no one answer, of course, and nature-nurture is always the question, but this is really interesting.

First, people who have dopamine receptors which require only normal amounts of dopamine are kinder and gentler than people who have the version of the gene which requires higher levels of dopamine to get the synapses to fire. That’s one study.

The other one is a little less direct: a gene which regulates brain cell division in utero also relates to unbridled aggression. Ok, so what? The brain cells are in the neighborhood of where we think our moral-center is: the frontal part of the brain. Is this the gene which allow us to “grow a conscience”?

I don’t know the answer, but here are the details.

Korean researchers combined a psychological test for trait anger with a genetic analysis of their dopamine receptor genes.

If a dopamine receptor gene has extra pieces of DNA in it, then the dopamine receptor protein (encoded by the gene) may be misshapen or may not be produced in sufficient quantity — and it may take more dopamine to actually bind to the receptor to get the synapse to fire in the neuron. For instance, the “7-repeat allele” — a dopamine receptor with seven extra pieces of DNA — is associated with ADHD (see the iHOP (Information Hyperlinked Over Proteins) database entry for DrD4 or the Wikipedia dopamine receptor genes entry, and scroll down for some references).

So, the researchers found, in their population, people who weren’t anger-holics and who were the live-and-let-live types had the dopamine receptor gene with few extra pieces of DNA (the “2-repeat allele”). The people who scored high on a trait-anger test had a higher number of DNA repeats (the “4-repeat allele”).

In addition, there is another gene which regulates brain stem cell division in the frontal part of the brain — so that when mice lacking this gene are born, they have all sorts of problems, including unbridled aggression. This type of research on the “orphan receptor” “NR2E1″ (also called “TLX”, see iHOP) is pretty new, but it looks like a variant of this gene — which controls brain cell growth in the developing embryo — may be associated with schizophrenia and bipolar among other conditions. To me, this is really really interesting because that may explain the whole anosognosia — the lack of insight into one’s illness. I was thinking it was white matter, but it may just be that this gene — which is located on the chromosome in the neighborhood of genes associated with schizophrenia and bipolar — may be the disconnect.

Association of DRD4 and COMT polymorphisms with anger and forgiveness traits in healthy volunteers. Kang JI, Namkoong K, Kim SJ
Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Although the biological basis of trait anger, anger expression, and forgiveness are not well understood, there has been growing evidence that anger-related dispositions are heritable and associated with genetic polymorphisms. The purpose of the present study was to investigate the possible relationship between anger and forgiveness traits and the dopamine receptor D4 (DRD4) and catechol-O-methyltransferase (COMT) Val158 Met polymorphisms in healthy Korean subjects. Three hundred and thirty-five healthy college students were recruited, and the 308 participants with a complete data set (184 males, 124 females) were included in the data analysis. DNA of the subjects was isolated from whole blood cells, and DRD4 variable number of tandem repeats and COMT Val158 Met polymorphisms were genotyped using polymerase chain reaction. Participants performed the State-Trait Anger Expression Inventory and Trait Forgivingness Scale measuring anger and forgiveness traits. The DRD4 2-repeat (2R) allele group had significantly lower anger in tendency and higher forgiveness traits than the 4R allele group in males. Our results provide evidence that the 2R allele of DRD4 in a Korean sample might have a different function from the 4R allele and a gender-specific role on anger-related traits. The COMT Val158 Met polymorphism had no significant relationship with anger and forgiveness traits. These findings suggest a possible relationship between anger expression styles and forgiveness traits and dopaminergic dysfunction.

Neurosci. Lett. (2008) PMID: 18063308

Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing.

Kumar RA, McGhee KA, Leach S, Bonaguro R, Maclean A, Aguirre-Hernandez R, Abrahams BS, Coccaro EF, Hodgins S, Turecki G, Condon A, Muir WJ, Brooks-Wilson AR, Blackwood DH, Simpson EM.

Centre for Molecular Medicine & Therapeutics and Child & Family Research Institute, Vancouver, British Columbia, Canada.

Nuclear receptor 2E1 gene (NR2E1) resides within a 6q21-22 locus for bipolar disorder and schizophrenia. Mice deleted for Nr2e1 show altered neurogenesis, cortical and limbic abnormalities, aggression, hyperexcitability, and cognitive impairment. NR2E1 is therefore a positional and functional candidate for involvement in mental illness. We performed association analyses in 394 patients with bipolar disorder, 396 with schizophrenia, and 479 controls using six common markers and haplotypes. We also performed a comprehensive mutation screen of NR2E1, resequencing its entire coding region, complete 5′ and 3′ untranslated regions, consensus splice-sites, and evolutionarily conserved regions in 126 humans with bipolar disorder, schizophrenia, or aggressive disorders. NR2E1 was associated with bipolar disorder I and II [odds ratio (OR = 0.77, P = 0.013), bipolar disorder I (OR = 0.77, P = 0.015), bipolar disorder in females (OR = 0.72, P = 0.009), and with age at onset </=25 years (OR = 0.67, P = 0.006)], all of which remained significant after correcting for multiple comparisons. We identified eight novel candidate mutations that were absent in 325 controls; four of these were predicted to alter known neural transcription factor binding sites. Analyses of NR2E1 mRNA in human brain revealed forebrain-specific transcription. The data presented support the hypothesis that genetic variation at NR2E1 may be associated with susceptibility to brain-behavior disorders. (c) 2008 Wiley-Liss, Inc.

PMID: 18205168 [PubMed – as supplied by publisher]


Nature. 2008 Jan 30 [Epub ahead of print]

A role for adult TLX-positive neural stem cells in learning and behaviour.

Zhang CL, Zou Y, He W, Gage FH, Evans RM.

[1] Howard Hughes Medical Institute, [2] Gene Expression Laboratory, and.

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

PMID: 18235445 [PubMed – as supplied by publisher]