This web page was produced as an assignment for an undergraduate course at Davidson College.

THE DISCOVERY OF THE "ANGER GENE": Could Anger Be a Hereditary Trait?

The Popular Press vs. Scientific Data

Good Morning America: Born to Get Angry

A story featured on Good Morning America in April 2002 stated that Dr. Redford Williams of Duke University had found evidence that anger might be a hereditary trait. The report claimed that “a tiny variation of a gene that we all carry will predict those more prone to anger." The report further stated that those who have the genetic variation are more likely to have blood pressures that can soar to dangerous levels and are at a greater health risk. Although this report did acknowledge that research in this area is still early, it is claimed that those who are more prone to anger can be identified based upon this particular genetic characteristic.

Permission to use this picture pending from ABCNews.com

The Research of Dr. Redford Williams:

According to Dr. Redford’s Williams’ research, central nervous system (CNS) serotonin function is involved in the regulation of potentially health damaging behavioral characteristics such as anxiety, depression, hostility and social isolation. In his study which was featured on Good Morning America, he evaluated the relationship between psychosocial/behavioral risk factors and two indices of serotonin function. CNS serotonin function can be indexed by levels of 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid (CSF) and previous research has shown that low CNS serotonin function is associated with impulsive and aggressive behaviors. Dr. Williams extracted 3-4 cc of CSF from all subjects in his study to determine their respective 5HIAA concentrations. Second, it is known that the serotonin transporter plays a crucial role in regulating the duration of central nervous system and peripheral actions of serotonin. A deletion/insertion polymorphism of the promoter region of the serotonin transporter gene (5HTTLPR) is associated with differential transcriptional efficiencies, as the basal and stimulated activity of the long allele (l) is approximately twice that of the short allele (s). Dr. Williams found that in a sample composed of predominantly white males, those with one or two copies of the long 5HTTLPR allele had CSF levels of 5HIAA that were 50% higher than persons with the short/short genotype. These persons with one or two copies of the long allele also exhibited greater blood pressure and heart rate responses to a mental stress protocol (Williams et al. 2001).

Figure 1: A schematic diagram of the human serotonin transporter protein. A polymorphism in the promoter region of the gene for the human serotonin transporter is what Dr. Williams' group believes contributes to hereditary anger-related characteristics. Permission to use this image is pending from the National Institute of Mental Health : http://intramural.nimh.nih.gov/research/lcs/research.html

Where is the Serotonin Transporter Gene Located?

The human serotonin transporter gene is located at the SLC6A4 locus on chromosome 17 (17q11.1-17q12), spans 31kbp and contains 14 exons. A variable number of tandem repeat (VNTR) element was found in the second intron and a 44bp insertion/deletion polymorphism has been identified in the transcriptional control region upstream of the serotonin transporter gene (Ohara et al. 1998). A gene containing the 44bp insertion in the transcriptional control region is considered to be the “long” form of the allele and a gene with the 44bp section deleted from the transcriptional control region is considered to be the “short” form of the allele. These definitions of “long” and “short” correspond with those identified by Dr. Williams in his study.  A study completed by Ohara et al. confirmed that the basal activity of the long allele promoter region was more than twice that of the short allele promoter region based upon a luciferase assay. However, unlike Dr. Williams’ study, the Ohara group was unable to identify any correlation between mood disorders and the presence of the long or short allele (Ohara et al. 1998).

Figure 2: Location of the serotonin transporter gene on human chromosome 17 as indicated by the red marking. For a more detailed view of the location of the serotonin transporter gene see NCBI Map Viewer.

Figure 3: Depiction of the "long" and "short" alleles of the serotonin transporter gene. Blue regions are exons, white regions are introns and the yellow regions represent the transcriptional control region of the gene. The terms "long" and "short" refer to the presence or absence of the 44bp insertion/deletion polymorphism in the transcriptional control region. A 17bp VNTR region is also located in second intron. This figure was generated based upon information presented by Ohara et al. 1998.

Is the Serotonin Transporter Gene Really the “Anger Gene?”

While several research groups have found evidence indicating that the polymorphic transcriptional control region of the serotonin transporter gene may contribute to anger-related behavioral characteristics, the story is much more complex than the feature story from Good Morning America leads us to believe. For instance, this particular polymorphism has not only been implicated as a gene likely to predict those more prone to anger, but other researchers have found countless other correlations between one's 5-HTTLPR genotype and the tendency to be depressed, develop schizophrenia, anorexia nervosa, and become suicidal among others. In addition, one research group emphasized the notion that two polymorphic regions of the serotonin transporter gene may regulate gene expression: the 44 base pair (bp) insertion/deletion in the promoter region (5-HTTLPR) and a 17 bp variable number of tandem repeat element in the second intron (VNTR-2) both seem to modulate the gene's transcription in an allele-dependent manner (Hranilovic et al., 2004). This indicates that both of these polymorphisms need to be taken into account, and perhaps other polymorphisms within this gene that have not been considered may also have a significant effect on gene expression and thus one's behavioral tendencies. Furthermore, groups which have studied the relation between the polymorphic region of the serotonin transporter gene and anger-related behavioral characteristics have often arrived at contradicting results. According to a study conducted by Lesch et al. in 1996, individuals with the short form of the serotonin transporter gene had higher neuroticism scores (e.g., anxiety, anger, hostility, depression, impulsiveness, worry and pessimism). In contrast, Dr. Redford Williams’ research indicates that those with the long allele of the serotonin transporter gene exhibited higher blood pressures and had greater heart rate responses to a mental stress protocol when compared to subjects that were homozygous for the short allele of the gene. It is also interesting to note that Good Morning America took quite a leap when claiming that Dr. Williams’ results would allow scientists and physicians to predict those more prone to anger-related behavioral characteristics. While increased heart rate and high blood pressure often accompany aggressive behavior, there was no direct measure of any anger-related behaviors in his study. Thus, the claims made by Good Morning America were extremely misleading and failed to convey the complexity of the issue. Furthermore, biologists are currently making an effort to depart from the one gene, one protein, one phenotype model to clarify the notion that phenotypes are produced by a variety of factors (both genetic and environmental) and that the expression of many traits is determined by the interaction of several genes.

Have Any Other Genes Been Shown to Be Related to Anger?

Several other studies have shown that genes other than the serotonin transporter gene may influence anger-related phenotypes. For example, one study determined that a functional polymorphism in Catechol-O-methyltransferase (COMT), an enzyme involved in catecholamine inactivation, may influence aggression-related traits via a bi-directional alteration of catecholamine turnover. Those who were heterozygous for the L allele (low activity allele which contains methionine at codon 108/158) and the H allele (high activity allele which contains a valine at codon 108/158) showed the lowest level of anger related traits, while those homozygous for either allele showed greater tendencies toward anger-related behavior (Rujescu et al. 2003). In addition, some groups have found that other genes in the serotongenic system other than the serotonin transporter gene might also be related to aggressive behaviors. For example, it has been reported that the A218C and the A779C small nucleotide polymorphisms in the typtophan hydroxylase gene (TPH gene), the rate limiting biosynthetic enzyme in the serotonin pathway, may be associated with anger-related characteristics (Rujescu, 2002).

Conclusions:

The ascertation by Good Morning America (ABC News) that with the finding of the "anger gene" we can predict those who are more prone to anger-related behavioral characteristics is extremely misleading. There are several reasons why this statement is far too simplistic. First and foremost, the research that the article was based upon did not make this claim. The study conducted by Dr. Redford Williams indicated that those with one or two copies of the long allele of the serotonin transporter gene had higher blood pressures and heart rates in response to mental stress, but their specific behavioral responses to stress were not mentioned. In addition, other scientific studies have shown that the polymorphism in the promoter region of the serotonin transporter gene may play a role in the determination of other behavioral tendencies such as depression, anorexia nervosa and suicidal tendencies. Thus, labeling the serotonin transporter gene as "the anger gene" creates the false implication that this particular polymorphism only directs those behavioral characteristics related to anger. It is also known that there are other polymorphisms within the serotonin transporter gene that have an effect on the gene's transcription, which were not considered in Dr. Williams' study. Other groups have found evidence that directly contradicts Dr. Williams’ research, indicating that more investigation needs to be done in this area in order to get a better understanding of the mechanisms by which this gene is regulated. Finally, some research has shown that anger-related characteristics are affected by other genes in the serotongenic system as well as the gene for the enzyme involved in catecholamine inactivation, not to mention the fact that more genes which have not been studied are likely to play a role in anger-related behavior. With all of this information, one can conclude that it is impossible for the serotonin transporter gene to be the "anger gene" as claimed by the Good Morning America report. While this gene may play a role in the determination of anger-related tendencies phenotypically, it is clear that there are multiple genes involved, making several of the statements made by the popular press inaccurate.

Important Links:

Serotonin Transporter Gene Sequence

OMIM - human serotonin transporter gene

References:

Hranilovic, D. et al. 2004. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry. 55(11): 1090-1094.

Manuck, S. et al. 1999. Aggression and Anger-Related Traits Associated With a Polymorphism of the Tryptophan Hydroxylase Gene. Biol Psychiatry. 45(5): 603-614.

Ohara, K. et al. 1998. Functional Polymorphism in the Serotonin Transporter Promoter at the SLC6A4 Locus and Mood Disorders. Biol Psychiatry. 44(7): 550-554.

Retz, W. et al. 2004. Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology.

Rujescu, D. et al. 2003. A Functional Single Nucleotide Polymorphism (V158M in the COMT Gene Is Associated with Aggressive Personality Traits. Biological Psychiatry. 54(1): 34-39.

Rujescu, D. et al. 2002. Association of anger-related traits with SNPs in the TPH gene. Molecular Psychiatry. 7:1023-1029.

Williams, R. et al. 2001. Central Nervous System Serotonin Function and Cardiovascular Responses to Stress. Psychosomatic Medicine. 63:300-305

2002. Born to Get Angry: Could Anger Be a Hereditary Trait? Good Morning America. April 29, 2002. <http://abcnews.go.com/sections/GMA/GoodMorningAmerica/GMA020429Anger_gene.html> Accessed 2004 6 September.

2003. 5-HTT: The Gene for Susceptibility to Depression? Rachel McCord's Genomics Web Page. Fall 2003. <http://www.bio.davidson.edu/courses/genomics/2003/mccord/5-HTT.html> Accessed 2004 6 September.