Scientific Reports 2, Article number: 677 doi:10.1038/srep00677
Received 13 June 2012 Accepted 04 September 2012 Published 20 September 2012
Both genetic and environmental factors have been shown to influence decision making, but their relative contributions and interactions are not well understood. The present study aimed to reveal possible gene-environment interactions on decision making in a large healthy sample. Specifically, we examined how the frequently studied COMT Val158 Met polymorphism interacted with an environmental risk factor (i.e., stressful life events) and a protective factor (i.e., parental warmth) to influence affective decision making as measured by the Iowa Gambling Task. We found that stressful life events acted as a risk factor for poor IGT performance (i.e., high reward sensitivity) among Met carriers, whereas parental warmth acted as a protective factor for good IGT performance (i.e., higher IGT score) among Val/Val homozygotes. These results shed some new light on gene-environment interactions in decision making, which could potentially help us understand the underlying etiology of several psychiatric disorders associated with decision making impairment.
Related: see Rs4680 – SNPedia a summary of Val158Met propensities
What Genes Tells Us About Worrying Another genetic explanation tells us less than meets the eye
on February 10, 2013 by Stanton Peele in Addiction in Society
Worrier or Warrior Gene? August 25, 2011
My mother in-law used to say “If you worry you die, if you don’t worry you die, so why worry”. She probably had the ‘warrior’ gene. None of her offspring are worriers either. Is it because they too have inherited the ‘warrior’ gene? Or is it because they learned first hand that worry is such a total waste of time.
The Sunday Times Magazine featured an article some time ago on Ozzy Osbourne of Black Sabbath fame. Ozzy had his genome sequenced. According to the article, Ozzy has both the worrier and warrior gene – a lot of people have one or the other, he has both. The way our genes are put together gives us information on what traits we’re likely to have and on the kinds of behaviors that we are likely to pass on to our kids. Ozzy discovered that “He has two versions of a gene known as COMT. The first is often called the ‘warrior variant’ and the second is known as the ‘worrier variant’.” Ozzy says that the presence of the “warrior” gene helps explain his legendry, high risk – often destructive behaviour, while evidence of a “worrier” gene explains his simultaneous tendency toward anxiety and insecurity. He reckons that the warrior part of him made him famous, while the worrier part has kept him alive. Many of his buddies who espoused the same lifestyle have long since bitten the dust.
For a more comprehensive view on the worrier versus warrior gene, you might like to take a look at a neuroscience paper on the subject: http://mbldownloads.com/1006CNS_Stein.pdf. A quote from the paper sums up the difference in characteristics between a worrier and a warrior. “Jolene was discussing her fraternal twin sons with her primary care physician. It was amazing how different they were. Jason loved to be outside, excelled at downhill skating, and looked forward to anything that involved thrills and spills (martial arts, roller coasters, etc.). John, on the other hand, loved reading, was superb at chess, and tried to avoid anything that involved possible injury (martial arts, roller coasters, etc.). She was quite sure that her sons had differed from birth; although she had provided them with the same home, they had developed different likes and different skills. She found it necessary to respond to them in entirely different ways in order to prevent the various excesses that each was prone to and to bring out the best in them.”
Warriors Versus Worriers: The Role of COMT Gene Variants by Dan J. Stein
“…catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val 158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158 ) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met
158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy).”
There is growing data on other polymorphisms in COMT which affect its activity. In addition, gene X environment interactions may act to affect function. For example, Val158 carriers show increased risk for developing schizophreniform disorder and psychotic symptoms if they have used cannabis during adolescence.25 A recent study of monozygotic twins26 found that there was considerable variation in the concordance of methylation of sites in the COMT gene. This epigenetic variation may reflect differences in environment, and may help explain differences in susceptibility to psychopathology in monozygotic twins.
Speculatively, COMT gene variants have particular evolutionary advantages. Val158 alleles may be particularly useful in threatening environments where maximal performance is required despite threat and pain (a warrior strategy). Met158 alleles appear to have evolved more recently and may be particularly useful in complex environments where maximal performance is required on tasks of memory and attention (a worrier strategy). The persistence of both variants may reflect the possibility that both warrior and worrier strategies can potentially be advantageous, depending on the circumstances.
Individual differences are not confined to superficial appearances; they more likely reflect crucial differences in underlying genes, circuits, and cognitive-affective function. Given the complexity of human behavior, one cannot expect that any gene variant is likely to explain a great deal of variance in phenotypes and the underlying mechanisms that contribute to explaining these phenotypes (endophenotypes). Nevertheless, when it comes to contrasting warriors with worriers, a growing set of studies suggests that specific variants in the COMT gene may play a crucial role in the embodiment of this distinction.
Carriers of at least one Val allele donated about twice as much money as compared with those participants without a Val allele (P = 0.01). Cooperativeness and the Val allele of COMT additively explained 14.6% of the variance in donation behaviour. Results indicate that the Val allele representing strong catabolism of dopamine is related to altruism.
The dopaminergic system is another target for the investigation of the genetic basis of prosocial behaviours because dopamine has been related to parenting behaviour (Lee et al., 2008; van IJzendoorn et al., 2008), affective modulation of emotional stimuli (Montag et al., 2008) and personality traits of positive emotionality (Reuter and Hennig, 2005; Reuter et al., 2006). There is also evidence that vasopressin interacts with dopamine in the genesis of prosocial behaviour: meadow voles characterized by promiscuity in contrast to the monogamous prairie voles, also show monogamous behaviour after injection of an AVPR1a vector into the pallidum. However, administration of a dopamine antagonist before the injection of the AVPR1a vector prevents this shift from promiscuous to monogamous behaviour in these animals (Lim et al., 2004). In the same line, facilitation of partner preference formation in voles by the activation of oxytocin receptors is not effective when dopamine D2 receptors are blocked (Liu and Wang, 2003). Therefore, it is plausible that dopaminergic gene variants have also an influence on other prosocial behaviours besides pair bonding. In the context of the dopaminergic neurotransmission, especially the COMT Val158Met polymorphism is an interesting candidate polymorphism because this gene locus has turned out to be functional. Catechol-O-methyltransferase is an enzyme which plays a crucial role in the metabolism of catecholamines by inactivating them in the synaptic cleft, mostly in the prefrontal cortex. A single nucleotide polymorphism (SNP), a G→A transition in codon 158 of the COMT gene located at the q11 band of human chromosome 22 (rs4680), results in 3- to 4-fold reduction in COMT enzyme activity by coding for the synthesis of the amino acid methionine (MET) instead of valine (VAL). Carriers of the Val/Val genotype have highest, carriers of the Met/Met genotype lowest and heterozygotes (Val/Met genotype) have intermediate levels of COMT activity (Lachman et al., 1996).
ONE IN EVERY THREE MEN HAS GOT THE WARRIOR GENE
A variation of a particular gene increases the risk of violent behaviour. A lot of men have got this gene variation, and it recently led to a reduction in the sentence given to a murderer in Italy.
By Ida Hammerich Nielson
One in every three men has got it: the warrior gene. But before you start worrying or wondering about your male colleagues or yourself, you need to hear the full story. Because the warrior gene only causes problems in men who have also had a difficult childhood.
This warrior gene, or the MAOA gene to give it the proper scientific name, is a variation of a specific gene whose function involves breaking down neurotransmitters in the brain. The variation means that the gene cannot break down these neurotransmitters very effectively, and this has consequences for human behaviour. Professor Anders Børglum from the Department of Human Genetics at the Faculty of Health Sciences explains that a number of studies now indicate that when coupled with a bad childhood, the warrior gene tends to lead to violent and anti-social behaviour.
“Several studies show with a good degree of certainty that you run a greater risk of developing anti-social behaviour if you have this gene variation as well as having had a difficult childhood. But the MAOA gene seems to have no effect if you have had a normal childhood. A few studies have revealed a small effect in such cases, but this has been impossible to confirm subsequently,” he says.
Gene reduces sentence
The warrior gene attracted media attention recently when an Italian judge reduced the sentence passed on a murderer by one year – based partly on scientific documentation of the killer’s genetic makeup, including the warrior gene. This was the first time in Europe that a judge had taken account of genetic analysis in passing sentence. In the USA in the past five years there have been about 200 cases in which the defence has tried to persuade the judge to consider the genetic makeup of people in the dock. However, this plea has only been successful in a few cases. Anders Børglum issues a powerful warning against using the warrior gene indiscriminately as an argument in court cases.
“The so-called warrior gene is only a tiny part of the whole genetic picture. People often have other genetic variations as well that reduce the importance of the warrior gene. The significance of the MAOA gene is far too small to say anything reliable about the risk of people developing anti-social behaviour. We need to do a lot more work before we can be certain about all this,” he concludes.
The researchers found that women with even just one copy of the low-expression type of MAOA were much happier than women with no copies. Meanwhile, many of the men in the study had a copy of the gene variant, but reported no more happiness than their peers without it, the researchers said.
The study, which appears in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry, controlled for various factors, including age, education and income.
“I was surprised by the result, because low expression of MAOA has been related to some negative outcomes like alcoholism, aggressiveness and antisocial behavior,” Chen said in a statement. “It’s even called the warrior gene by some scientists, but, at least for women, our study points to a brighter side of this gene.”
Happiness Gene Discovered In Women, Says New Study
The Huffington Post | By Emma Gray
Researchers from the University of South Florida, Columbia University and the National Institutes of Health found that a type of the monoamine oxidase A (MAOA) gene was connected to higher levels of self-reported happiness in women. The study, published this month in the journal Neuro-Psychopharmacology & Biological Psychiatry, looked at the DNA of 193 women and 152 men, reported Fox News. Researchers then compared these results to the participants’ levels of self-reported happiness, controlling for factors such as age, gender, race, income, marital status, self-esteem and physical health. Women with at least one copy of the low-expression version of the MAOA gene reported significantly higher levels of happiness than women without the gene as well as men both with and without the gene.
Hamian Chen, an associate professor at the USF College of Public Health and the study’s lead author, expressed surprise at the results in a press release. Happiness isn’t the only attribute that the MAOA gene has been linked to. “I was surprised … because low expression of MAOA has been related to some negative outcomes like alcoholism, aggressiveness and antisocial behavior. It’s even called the warrior gene by some scientists, but, at least for women, our study points to a brighter side of this gene.”
Chen and his research team said they believe that the reason for this connection is that the MAOA gene allows larger amounts of dopamine, serotonin and other mood-elevating neurotransmitters to stay in the brain. (These are the same neurotransmitters that are released during orgasm, and really, who doesn’t have their mood lifted during the big O?)
The scientists said they hope that this study will shed light on gender differences in happiness. Although women experience mood and anxiety disorders more frequently than men do, according to the study press release, women’s self-reported happiness tends to be higher than men’s across the board.
Previous research on happiness has found mixed results when it comes to gender. A 2007 feature in the New York Times reported “a growing happiness gap between men and women” — with men coming out on top….
Pity the poor murderer, his genes made him do it
Did his genes make him murder? July 13, 2010 by Nigel Barber, Ph.D. in The Human Beast
Can Your Genes Make You Murder?
by BARBARA BRADLEY HAGERTY
July 01, 2010
The Maori, MAO Inhibitors, and the “Warrior Gene” by Shelley Batts on August 10, 2006
“New Zealand’s indigenous Maori population reacted angrily on Wednesday to a researcher’s findings that Maori have a high representation of a gene linked to aggression, as the nation faces a domestic violence crisis.”
According to a Yahoo news story, genetic epidemiologist Rod Lea recently presented research in Australia that Maori men were twice as likely to carry monoamine oxidase than European men, describing it as “the warrior gene.” This gene has apparently been tied to aggression and risk-taking behaviors such as smoking and gambling.
“I believe this gene has an influence on behavior of humans in general, but I also believe that the influence is rather small,” Lea told New Zealand’s National Radio on Wednesday.
“We have to be clear that behavioral traits such as susceptibility to addiction, aggressive behavior, risk taking, all those sort of things, are extremely complex and they are due to numerous factors including non-genetic environmental factors like upbringing and other lifestyle factors,” he said.
The Maori people are concerned that this will only serve to confirm stereotypes regarding their tribe: that they are violent, aggressive, with high crime and domestic violence rates. However, there is a persistent problem with domestic violence; the New Zealand government found that Maori children under 5 years old are twice as likely to be admitted to the hospital for an “intentional injury” than other groups.
Now this news piece did a not-so-great reporting job on the science. I think what they meant to say was that Maori men were more likely to carry the gene that encodes monoamine oxidase (MAOs; although there are two types MAO-A and MAO-B), which are both located on the X chromosome. MAO-A and MAO-B are attached to the outer membrane of the mitochondria and function to oxidize amine neurotransmitters such as dopamine and serotonin.
MAOs are extremely important for proper brain function as they inactivate neurotransmitters. When MAOs are in over abundance, there is too much inactivation of neurotransmitters. Neurological disorders like depression, criminal behavior, phobias, ADD, and addiction can arise. In fact, a major treatment for depression is MAO inhibitors, and these drugs are also given to Parkinson’s patients to enhance the effectiveness of dopamine replacement through L-Dopa. MAOs also increase with age, and apoptotic cells (dying cells) often have increased MAOs as well.
But back to the Maori, what seems to be suggested is that they have an increased incidence of MAO genes resulting in more MAO produced as compared to other populations. As the researcher himself notes, the gene may exert some influence but behavior is complex—it results from environment as well. Perhaps the Maori are overlooking a really useful bit of information here: MAOs can be inhibited. If it is shown to be true that MAOs can increase aggressiveness, depression, etc, high-risk individuals could be treated with MAO blockers.
A Neuroscientist Uncovers A Dark Secret
by BARBARA BRADLEY HAGERTY
June 29, 2010
Jim Fallon’s family experiment. Along with brain scans, Fallon also tested each family member’s DNA for genes that are associated with violence. He looked at 12 genes related to aggression and violence and zeroed in on the MAO-A gene (monoamine oxidase A). This gene, which has been the target of considerable research, is also known as the “warrior gene” because it regulates serotonin in the brain. Serotonin affects your mood — think Prozac — and many scientists believe that if you have a certain version of the warrior gene, your brain won’t respond to the calming effects of serotonin.
Fallon calls up another slide on his computer. It has a list of family members’ names, and next to them, the results of the genotyping. Everyone in his family has the low-aggression variant of the MAO-A gene, except for one person.
“You see that? I’m 100 percent. I have the pattern, the risky pattern,” he says, then pauses. “In a sense, I’m a born killer.”
Fallon was prompted to study his brain after his mother, Jenny, told him his ancestry was full of alleged murderers.
Courtesy of Jim Fallon
Fallon’s being tongue-in-cheek — sort of. He doesn’t believe his fate or anyone else’s is entirely determined by genes. They merely tip you in one direction or another.
B. Lajin, A.A. Sakur, A.R. Hamzeh and A. Alachkar, 2010. Genotype Distribution of the Single Nucleotide Polymorphism Val158Met of the COMT Gene in the Syrian Population. Journal of Biological Sciences, 10: 701-704. DOI: 10.3923/jbs.2010.701.704
The transition from G to A at nucleotide 21881 of the COMT gene is a functional single nucleotide polymorphism (Val158Met). The produced enzyme which contains Methionine in place of Valine has lower enzymatic activity that has been associated with greater risk for developing psychiatric disorders….Allele frequencies were calculated and found to be 47 and 53% for the Val and Met allele, respectively. The calculated frequencies were compared to other populations and were found to be closest to those of the Caucasian populations and farthest from those of the East Asian and African populations.
A study in Denmark of boys adopted from 1927 to 1947 revealed a strong correlation between felony convictions among biological parents and their children, even though adoptive parents had to be free of felony convictions in order to adopt.
Bhakta SG The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophr Res. 2012 Sep;140(1-3):192-7. doi: 10.1016/j.schres.2012.06.026. Epub 2012 Jul 10.
The Met158 allele of the COMT gene confers a significantly increased risk for aggressive and violent behavior in schizophrenia. These data may provide basis for developing informative strategies for reducing violence in patients with schizophrenia.
De Luca V, Tharmalingam S, Sicard T, Kennedy JL. Gene-gene interaction between MAOA and COMT in suicidal behavior. Neurosci Lett. 2005;383:151-154.
Zahn-Waxler C. Warriors and worriers: gender and psychopathology. Dev Psychopathol. 1993;5:79-89.
Brook JS, Whiteman M, Cohen P. Warriors and worriers: a longitudinal study of gender differences in drug use. NIDA Research Monographs. 2000;271-284.
Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. M R Munafò, L Bowes, T G Clark, J Flint, Molecular Psychiatry (impact factor: 13.67). 09/2005; 10(8):765-70. DOI:10.1038/sj.mp.4001664
ABSTRACT There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent meta-analysis that reported an association of the catechol O-methyltransferase
Olsson CA, Anney RJ, Lotfi-Miri M, et al. Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet. 2005;15:109-115.
Kunugi, H., S. Nanko, A. Ueki, E. Otsuka and M. Hattori et al., 1997. High and low activity alleles of catechol-Omethyltransferase gene: Ethnic difference and possible association with Parkinson`s disease. Neurosci. Lett., 221: 202-204.
Ohara, K., M. Nagai, Y. Suzuki and K. Ohara, 1998. Low activity allele of catechol-O-methyltransferase gene and Japanese unipolar depression. Neuroreport, 9: 1305-1308.
Patients with depressive disorders exhibited a significantly higher rate of genotypes with the COMTL allele than healthy controls (p = 0.012), which was not the case in patients with bipolar disorders. The presence of the COMTL allele was significantly associated with depressive disorders (odds ratio 2.19, 95% CI 1.19-4.03). Our results suggest the COMTL allele contributed to the etiologies of depressive disorders.
Ohmori, O., T. Shinkai, H. Kojima, T. Terao, T. Suzuki, T. Mitab and K. Abea, 1998. Association study of a functional catechol-O methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci. Lett., 243: 109-112.
We investigated a genetic association between schizophrenia and the COMT gene polymorphism in 150 Japanese schizophrenics and controls. We detected the low activity met-108 allele more frequently in schizophrenics than in the controls, and found that subjects sharing the met-108 allele (val/met and met/met) are significantly more common in the patients than in the controls. The results suggest that the low activity met-108 allele may be involved in susceptibility for schizophrenia
Wilder RM, Volavka J, Czobor P, et al. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry. 2002;52:701-707.
Malhotra AK, Kestler LJ, Mazzanti C, et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry. 2002;159:652-654.
Heinz A, Smolka MN. The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks. Rev Neurosci. 2006;17:359-367.
Xu K, Ernst M, Goldman D. Imaging genomics applied to anxiety, stress response, and resiliency. Neuroinformatics. 2006;4:51-64.
Tunbridge EM, Harrison PJ Weinberger DR. Catechol-o-Methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006;60:141-151.
Crampton, P., & Parkin, C. (2007, March 2). Warrior genes and risk-taking science. Journal of the New Zealand Medical Association, 120 (1250).
McDermot, R., et al. (2009). Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation. Proceedings of the National Academy of Sciences, 106, 2118-2123.
Caspi, A. et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851-854
Karayiorgou, M., M. Altemus, B.L. Galke, D. Goldman, D.L. Murphy, J. Ott and J.A. Gogos, 1997. Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive compulsive disorder. Proc. Natl. Acad. Sci. USA., 94: 4572-4575.
Anand Tamatam, Genetic biomarkers of depression
Indian J Hum Genet. 2012 Jan-Apr; 18(1): 20–33.
Genetic factors have been implicated in the etiology of depression and many studies have determined that changes in protein structure correlate with a predisposition to specific conditions. More than 10 million single nucleotide polymorphisms (SNPs) have been identified in humans; however, the importance of most SNPs for health and disease is not understood. Most SNPs are indeed unimportant and because of often inadequately powered studies, many observations on SNP effects cannot be repeated by other researchers. SNPs are at best shown to influence protein function or level, rarely to influence risk of disease, and almost never to influence total mortality, the ultimate endpoint. However, specific genes or relevant DNA sequence variations involved in the pathogenesis of depression have not yet been identified.
Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. MDD and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic–pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene brain-derived neurotrophic factor (BDNF).
MDD has been a growing public health concern due to its recurrent, deliberate, and lethal nature. According to projections, MDD will become the second leading cause of disability worldwide by the year 2020. By the year 2030, it is estimated to be the highest cause of disability in high-income countries and still the second cause of burden of disease globally. Having been recognized as a multifactorial disease, the total contribution of genetic factors in the origin of disease, the heritability, is estimated at nearly 40%. Notably, the mode of inheritance is complex and ambiguous. Thus, relevant DNA sequence variations in poten-tial candidate genes contributing to the susceptibility to MDD remain to be explored. Studies on norepinephrine and serotonin pathways have highlighted the molecular role of these neurotransmitter systems in the pathophysiology of MDD. Nevertheless, the role of dopamine (DA) neurotransmission in MDD has gained increasing attention since the earliest report in the mid-1970s. Clinically, changes in both serotonergic and dopaminergic activity have been observed in patients with MDD receiving long-term treat-ment with antidepressants. Also, therapy using dopaminergic agents in treatment-resistant patients with MDD has been demonstrated to enhance the action of antidepressant medications. Furthermore, antidepressants with direct dopaminergic effects have been well documented. Research findings have consistently emphasized the molecular connection between genes associated with dopaminergic activity and the pathophysiology of MDD.[16,17] The dopaminergic system, which consists of DA-producing cells, DA receptors and DA transporters (DAT1, also referred to as SLC6A3), may play a crucial role in MDD. In particular, DAT1 proteins play a significant role in the reuptake of DA into presynaptic neu-rons and limit the duration of synaptic activity, thus being the key regulators of DA level in the brain. In humans, the DAT1 gene, located at chromosome 5q35.1, contains 15 exons,[18,19] and its expression occurs in all DA neurons, including those originating in the substantia nigra and ventral tegmentum. Although several lines of evidence suggest an association between DA and MDD, few studies have directly explored the molecular link between MDD and polymorphisms in such main dopaminergic gene as DAT1. Until recently, the C/T single nucleotide polymorphism (SNP) in intron 14 of the DAT1 gene, also referred to as rs40184, has been demonstrated to moderate the effect of perceived ma-ternal-rejection on the onset of MDD, as well as on suicidal ideation, thus signifying a gene-by-environment (G × E) interaction in the etiology of MDD. This particular SNP has also been found to play a genetic role in certain neuropsychiatric and neurological illnesses such as attention deficit hyperactivity disorder, bipolar disorder, and migraine with aura.
The norepinephrine transporter (NET), a Na/Cl-dependent substrate specific transporter, terminates noradrenergic signaling by rapid reuptake of neuronally released norepinephrine into presynaptic terminals. NET exerts a fine regulated control over norepinephrine-mediated physiological effects such as depression. As the 50 flanking promoter region of the NET gene, NET T-182C, contains several cis elements that play a critical role in transcription regulation,[24,25] changes in this promoter DNA structure may lead to an altered transcriptional activity responsible for a predisposition to MDD. Although a silent G1287A polymorphism, located at exon 9 of the NET gene, is not an important factor in susceptibility to depression in a Japanese population, but it cannot be denied that it may be an important candidate. BDNF is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (SNP rs6265) in MDD have produced inconsistent results. Meta-analysis of studies compared the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and non-depressed controls. MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. In order to further clarify the impact of BDNF gene variation on major depression as well as antidepressant treatment response, association of three BDNF polymorphisms [rs7103411, Val66Met (rs6265) and rs7124442] with major depression and antidepressant treatment response was investigated. All SNPs had main effects on antidepressant treatment response. Results do not support an association between genetic variation in BDNF and antidepressant treatment response or remission.
Preliminary studies suggest a potential minor role of genetic variation in BDNF and antidepressant treatment outcome in the context of melancholic depression. Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or antidepressant response. Novel single-nucleotide polymorphisms (SNPs), untranslated regions, in coding sequences, in introns, and upstream regions; 3 of 4 rare novel coding SNPs were non synonymous. Association analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and two haplotypes in different blocks (one including Val66, another near exon VIIIh) were significantly associated with MDD.
Alterations in BDNF-signaling pathways may play an important role in the pathophysiology of MDD. Five SNPs in three BDNF signal-transduction pathway genes (BDNF, GSK3B, and AKT1) were used in association analyses. An allelic association between the GSK3B SNP rs6782799 and MDD was found in our samples. Further gene-gene interaction analyses showed a significant effect of a two-locus BDNF/GSK3B interaction with MDD (GSK3B rs6782799 and BDNF rs7124442) and also for a three-locus interaction (GSK3B rs6782799, BDNF rs6265, and BDNF rs7124442). These findings support the assertion that the GSK3B gene is an important susceptibility factor for MDD in a Han Chinese population.
Mounting evidence shows that brain-derived neurotrophic factor (BDNF) plays a crucial role in synaptic plasticity. Normally, BDNF sustains the viability of brain neurons. Under stress, however, BDNF gene is repressed, leading to atrophy and possible apoptosis of vulnerable neurons in the hippocampus when their neurotrophic factor BDNF is absent. These events in turn lead to depression and to the consequences of repeated depressive episodes, namely, more and more episodes and less and less responsiveness to treatment. Due to its potential involvement in psychiatric diseases such as depression, BDNF became a major target in research. A functional polymorphism of the BNDF Val66Met influences and reduces trafficking and secretion of BDNF protein in the brain and is thought to be associated with low BNDF levels in MDD.[33–36]
The monoamine hypothesis proposes that depression is due to a deficiency in monoaminergic neurotransmission. Developed out of a meticulous research effort in modern psychiatry, the monoamine hypothesis is an early milestone in the field of depression. Under this hypothesis, depression is postulated to reflect a deficiency or imbalance in noradrenaline or serotonin. Several antidepressant drugs increased synaptic concentrations of noradrenaline or serotonin and that reserpine, a catecholamine-depleting drug, could cause depression-like symptoms. Catecholamine depletion by dietary methods has also been shown to induce a relapse of depressive symptoms. Subsequent variations of the monoamine hypothesis were supported by animal research, including the findings that antidepressants effectively treat learned helplessness. Currently, the evolving monoamine hypothesis considers the possibility that depression may be linked to a deficiency in signal transduction from the monoamine neurotransmitter to its postsynaptic neuron in the presence of normal amounts of neurotransmitter and receptor.
The 5-HTT gene regulates brain serotonin neurotransmission by removing the neurotransmitter from the extracellular space. Since the development of the selective serotonin reuptake-inhibitors, a putative role for 5-HTT in the etiology of depression has been explored. The discovery of a functional 5-HTT polymorphism has provided a novel tool to further scrutinize the role of serotonergic neurons in depression. A repeat of 20-23 base pairs has been observed as a motif within a polymorphic region of the 5-HTT gene and it occurs as two prevalent alleles: one consisting of 14 repeats (S allele) and another of 16 repeats (L allele). This functional polymorphism in the promoter region, termed 5-HTTLPR, alters transcription of the serotonin transporter gene. The S allele leads to less transcriptional efficiency of serotonin[37,38] and it can partly account for anxiety-related personality traits.
Two serotonin 2A receptor (HTR2A) SNPs recently reported to be associated with antidepressant treatment response in STARD (rs7997012; rs1928040) for association with treatment response in two independent Caucasian samples of patients with a Major Depressive Episode. SNP rs7997012 was significantly associated with remission after 5 weeks providing first replicative support for the initial finding, with however, an inverse allelic association as compared to the STARD sample. Another common polymorphism is a variable number tandem repeat (VNTR) in intron 2 (STin2), which has three alleles consisting of either 9 (STin2.9), 10 (STin2.10), or 12 (STin2.12) repeats, were shown to be in linkage disequilibrium, with the positive association between the STin2 allele 10 and the 5-HTTLPR L allele. Variation at the VNTR can also influence expression of the transporter with the polymorphic VNTR regions acting as transcriptional regulators although it is likely to have no significant effect on function. Tryptophan hydroxylase (TPH) is the enzyme involved in the biosynthesis of serotonin. It catalyzes the oxygenation of tryptophan to 5-hydroxytryptophan, which is decarboxylated to serotonin. It is thus the rate-limiting enzyme in the biosynthesis of serotonin. Changes in the metabolism of the essential amino acid tryptophan play an important role in the brain-endocrine-immune system interaction that is hypothesized to be involved in the pathophysiology of MDD. There are two main pathways of tryptophan metabolism: one is the serotonin pathway and the other is the kynurenine (KYN) pathway. Dysfunction of the serotonergic system has been hypothesized to play an important role in depression. The higher serotonergic activity during stress leads to a higher breakdown of serotonin. Sustained stress will lead to diminution of serotonin (synthesis/degradation). Thus, chronic stress may lead to functional shortage of the supply of serotonin. Two genes have been discovered which encode for the TPH isoforms (TPH1 and TPH2). Most of the molecular genetic studies on the TPH genes so far have examined the two polymorphisms of the TPH1, A218C and A779C, which have been found to be in complete or strong linkage disequilibrium in previous studies. A polymorphism in intron 7 of TPH1, A218C, has been extensively examined in association studies, and the A allele is associated with anxiety symptoms in depression. There is no association between the TPH2 polymorphisms and stress-induced depression.[46,47] Catechol-O-methyltransferase (COMT) is an important enzyme involved in the degradation of catecholamine neurotransmitters
Depression is thought to involve, in part, dysregulation of serotonergic neurotransmission. A Val158Met polymorphism affects the activity of the COMT enzyme and individuals with the Val/Val genotype have a 3–4 times higher enzyme activity than those with the Met/Met genotype. One of the European study reported an association between the Val/Val genotype and early onset MDD, but conflicting results have been found in other studies with fewer participants. As serotonin exerts its effect on specific receptors on the postsynaptic membranes, the serotonin receptor (5-HTR) genes are considered good candidates. The 5-HTRs affect the release and activity of other neurotransmitters such as glutamate, DA, and gamma-aminobutyric acid (GABA). There are seven main types of 5-HTRs. Including subtypes, there are a total of at least 14 different receptors based on their pharmacological responses to specific ligands, sequence similarities at the gene and amino acid levels, gene organization, and second messenger coupling pathways. Several subtypes, including the 5-HTR1A, 5-HTR1B, 5-HTR2A, 5-HTR3, and 5-HTR4, act to facilitate neurotransmitter DA release, while the 5-HTR2C receptor mediates an inhibitory effect of serotonin on DA release. Most 5-HTR subtypes only modulate DA release when serotonin and/or DA neurons are stimulated, but the 5-HTR2C, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. The 5-HTR1A is an important member of the large family of serotonin receptors. The 5-HTR1A is located both at a postsynaptic and at a presynaptic level, in the first case, they mediate the action of serotonin on cortical and limbic neurons and in the second case, they act as serotonergic autoreceptors on serotonergic neurons in the raphe nuclei and prevent the release of serotonin by negative feedback. In depressed individuals, the number of serotonin receptors, including the 5-HTR1A autoreceptors, is increased. A common functional polymorphism C-1019G in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. DOPA decarboxylase is an enzyme implicated in two metabolic pathways, synthesizing two important neurotransmitters, DA and serotonin.
Receptors that couple to G proteins communicate signals from a large number of hormones, neurotransmitters, chemokines, and autocrine and paracrine factors.
Many important hormones and neurotransmitters, including epinephrine, acetylcholine, DA, and serotonin, use the Gi and Go pathways to evoke physiological responses. In vitro and in vivo studies suggested that the -141C Ins/Del polymorphism may be directly responsible for the regulation of DRD2 expression and DRD2 function. Ser311Cys in DRD2 has been reported to be associated with a reduced ability of activating the appropriate Gi-like protein. Brain imaging studies of healthy volunteers have shown that individuals with an A1 allele (C allele of C32806T) of DRD2 have a reduced number of dopamine D2 receptors.[69,70] The DRD3 Ser9Gly genotypes were reported to differ with regard to their DA-binding affinity. The most widely studied polymorphism of DRD4 is a 48-bp variable number of tandem repeats (VNTRs) which encodes for the third intracytoplasmic loop and contains 2–11 repeats. A 48-base pairs repeat in exon 3 of DRD4 was associated with the potency of inhibition of cAMP formation by DA. The DRD4 48-base pairs repeat in the exon 3 was significantly associated with major depression while the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms were not. These polymorphisms may be hypothesized to influence MDD. These polymorphisms have been reported to increase the susceptibility to depression, although negative findings have also been reported.
Since then, several studies have reported a link between MDD, or depressive symptoms, and a variety of inflammatory and immune biomarkers.[96–98] Depression may cause inflammation through altered neuroendocrine function and central adiposity. However, depression may also be a consequence of inflammation, since a pathogenic role of inflammatory cytokines in the etiology of depression has been described. Although given less consideration, a third possibility is that depression is a marker of some other underlying dimension that is separately linked to depression and inflammation. Recently, it has been proposed that such underlying factor could be a specific genetic makeup.
MPO is an enzyme of the innate immune system, which exhibits a wide array of proatherogenic features. MPO is secreted upon leukocyte activation, contributing to innate host defenses. However, it also increases oxidative stress, thereby contributing to tissue damage during inflammation and atherogenesis. MPO generates numerous reactive oxidants that cause lipid peroxidation, posttranslational modifications to target proteins, and decrease of nitricoxide bioavailability resulting into oxidation of low density lipoproteins LDL and apolipoprotein A1, protein carbamylation, and endothelial dysfunction. Transgenic mice containing the human MPO gene show significantly larger atherosclerosis build up than the wild type. In humans, individuals with total or subtotal MPO deficiency, a defect with a frequency of 1 in every 2000 to 4000 whites, are less likely to develop cardiovascular diseases and those harboring a promoter polymorphism associated with a 2-fold reduction in MPO expression appear cardioprotected. Oxidative stress has also been linked to neuronal degeneration in the central nervous system. MPO is both expressed and enzymatically active in the human brain and is associated with Alzheimer’s disease. Earlier studies have described abnormalities of oxidant–antioxidant systems in MDD suggestive of higher oxidative stress. For example, elevated levels of antioxidant enzymes, particularly superoxide dismutase (SOD) and biomarkers of oxidation, such as malondialdehyde, were found in plasma, red blood cells, or other peripheral tissues of acutely depressed MDD patients compared with controls. In some cases, but not others, these abnormalities were reduced with antidepressant treatment. SOD coenzyme concentrations are also higher in postmortem brain tissue (prefrontal cortex) of MDD patients than in control brains. Overall, twins with MDD had 32% higher levels of MPO than those without MDD, an association that was not explained by other risk factors. Other inflammatory biomarkers, except TNF-α, tended to be elevated in twins with MDD…
Kunugi H, No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene. Biol Psychiatry. 1997 Aug 15;42(4):282-5.
Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample
Fan JB, Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis.Biol Psychiatry. 2005 Jan 15;57(2):139-44.
A common functional polymorphism (Val/Met) in the catechol-O-methyltransferase gene (COMT) that markedly affects enzyme activity has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans. It is hypothesized that the high activity Val allele slightly increases risk for schizophrenia through its effect on dopamine-mediated prefrontal information processing.
We compared the allele/genotype frequencies of the Val/Met polymorphism in a large independent patient-control sample (862 patient and 928 healthy control subjects) from Han Chinese population, and an update meta-analysis was performed to assess the collective evidence across individual studies.
No statistically significant differences were found in allele or genotype frequencies between patient and normal control subjects, although a nonsignificant overrepresentation of the Val allele in schizophrenia patients (odds ratio [OR] = 1.09, 95% confidence interval [CI] = .94-1.26) was suggested. Comparatively, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among the group of studies. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the Val allele in Asian population (OR = .96, 95% CI = .85-1.09), nor in European population (OR = 1.06, 95% CI = .95-1.19).
Our data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations.
Wu, Lijuan, Association study of the Fyn gene with schizophrenia in the Chinese-Han population Psychiatric Genetics: February 2013 – Volume 23 – Issue 1 – p 39–40 doi: 10.1097/YPG.0b013e328358640b
Fang C Family-based association studies of CAPON and schizophrenia in the Chinese Han population.Progress in Neuro-psychopharmacology & Biological Psychiatry [2008, 32(5):1210-1213] (PMID:18430503)
Although there is evidence pointing to CAPON as a susceptible gene for schizophrenia, the results of independent association studies have so far been inconsistent. A recent case-control study by Zheng et al. supported CAPON as a susceptible site for the disease in the Chinese Han population. In their study both the single polymorphism (rs348624) and individual haplotypes showed significant association with schizophrenia. Our study further investigates this relationship this time using a family-based association. We selected 5 SNPs including rs348624 and performed a Transmission Disequilibrium Test (TDT) in 319 Chinese Han trios. Our results identified no single marker nor haplotype associated with schizophrenia, which did not suggest that CAPON was a susceptible site in the Chinese Han population, or it appeared unlikely that the CAPON played a major role in the aetiology of schizophrenia. Since there is consistent evidence pointing to 1q21-22 as a positional candidate region for schizophrenia, we suggest that further research should focus on other genes located in this region.
These results show that (1) there is a significant relationship between the COMT gene, the levels of Cortisl and the performance (sales competences), (2) that there is an indication that worriers (Val / Val allele) could be less sensitive to stressful situations and (3) that there is an indication that a optimum of level of Cortisol exist on which people perform the best. These conclusions always have to be seen in perspective to the research and the experiment and that is why it is possible to say that these three conclusions can be drawn for this data.
John Thompson: Are High Stakes Tests Here to Stay? Guest post by John Thompson.
“High-stakes academic testing isn’t going away,” argues Po Bronson and Ashley Merryman in their New York Times Magazine article “Why Some Kids Handle Pressure while Others Fall Apart?” They describe a 5th grader’s ordeal with standardized testing, “He got headaches and stomachaches. He would ask not to go to school.” His pre-test anxiety “lasted a solid month before the test” and “‘even after the test, he couldn’t let it go.'”
Their answer is “more competition. It just needs to be the right kind.” Of course, such a response would obviously be condemned as cruel unless “high-stakes academic testing isn’t going away,” so we have to get used to it.
Bronson and Merryman admit that “even third graders feel as if they are on trial. Students get the message that class work isn’t what counts, and that the standardized exam is the truer measure. Sure, you did your homework and wrote a great history report — but this test is going to find out how smart you really are.” Their answer, however, is “training, preparation and repetition” to overcome such a “curse.”
Bronson and Merryman argue that something called the COMT gene that divides us into the quarter of people with “Warrior-only genes,” and the quarter who are “Worrier-only.” However, they claim we can train a student to become a “Worrier-gene Warrior” and, presumably, that is the purpose of schooling in a global market.
Like Bill Gates and the “Billionaires Boys Club,” they argue that “some children actually do better under competitive, stressful circumstances.” Who could argue with that? But, why should those “Warriors” impose stressful competition on all children?
Bronson and Merryman describe a soccer player at a charter school, who injured his knee playing football, but who used his competitive energy to excel at standardized testing. Who would deny parents the right to choose charter schools that create “a competition in which the only thing anyone cares about is the final score?”
But, even in those schools, parents must sign a permission slip before their kids engage in the risks of football. Nobody seeks authorization by parents in public schools before imposing bubble-in accountability. Should parents not have to grant permission before a school imposes a system that produces so many harmful side effects?
Let’s think about the pedagogy proposed by Bronson and Merryman. They admit that standardized testing can produce such anxiety that students must subsequently “acclimate to recurring stressors.” Parents must sign off on other vaccines but not their kids’ “stress inoculation.” In an age of “reform,” it is up to schools to decide how much to tax children without overwhelming them. They must “then allow for sufficient recovery.”
Bronson and Merryman present a 21st century version of, “the Battle of Waterloo was won on the playing fields of Eton.” If they, or school reformers, think our democracy has gone soft because we watch too much of PBS’s “Downton Abbey,” they can sign their own kids up for rugby. If their own kids’ school wants a metric that keeps students from being “shielded from all challenge,” that’s up to them. Rather than distort children’s classroom, I’d just require them to ride a bull for eight seconds. Even if Bronson and Merryman are correct, wouldn’t it be more humane to replace high-stakes testing with a Ultimate Fighting Championship club. Perhaps I’m just a worrier, but I’d prefer my kids suffering a broken jaw or a ruined knee than having the joy driven out of learning
On the other hand, when Bronson and Merryman throw down this gauntlet, they bring out my inner warrior. I’m going to use their sole rationale for their brand of test prep the way a football coach uses an opponent’s words to fire up his team. “High-Stakes Academic Testing Isn’t Going Away!”
The response of “High-Stakes Academic Testing Isn’t Going Away!,” says all we need to know about “reformers'” disregard for educational values. Competition trumps the exchange of ideas. So, get over it. Parents, it might be your child who is “particularly ill suited” for high-stakes testing in 3rd grade. But, we’ll teach her to get over it. Teachers, you might not like to impose so much anxiety on children. But, “High-Stakes Academic Testing Isn’t Going Away!” so, get over it.
What do you think? Given the dangers which Bronson and Merryman acknowledge as side effects of high-stakes testing, shouldn’t schools seek parents’ permission before allowing it? And, is it true that “High-Stakes Academic Testing Isn’t Going Away!” so we need to teach ways to get over it?
John Thompson was an award winning historian, with a doctorate from Rutgers, and a legislative lobbyist when crack and gangs hit his neighborhood, and he became an inner city teacher. He blogs for This Week in Education, the Huffington Post and other sites. After 18 years in the classroom, he is writing his book, Getting Schooled: Battles Inside and Outside the Urban Classroom
The genetics of addictions: uncovering the genes David Goldman