PKCI/HINT1 (University of Baltimore Maryland, 2009) – mice without this gene tended to give up more quickly to escape unpleasant circumstances, leading researchers to nickname it the “despair” gene. Those who possessed the gene exhibited a borderline-abnormal persistence in attempting to escape from these circumstances.
They also tended towards lower levels of anxiety. The researchers do not know why eliminating the gene has this effect but they believe it could be helpful in studying the phenomenon of mania. The gene is concentrated a great deal in the brain. The researchers say that cadavers of those who had been diagnosed with schizophrenia and bipolar disorder had lower concentrations of the gene in their brains.
MKP-1 (Yale University, 2010) – Depressed individuals, according to Yale researchers, have more than twice as much MKP-1 expressed in their brains. The gene also deactivates a molecular pathway that is important to neuron survival and function. Mice without the gene become resilient to stress, but when the gene is activated, they become prone to depression.
ew study reveals a novel gene associated with major depression. The research, published in the April 28 issue of the journal Neuron, suggests a previously unrecognized mechanism for major depression and may guide future therapeutic strategies for this debilitating mood disorder.
SLC6A15 (Cell Press, 2011) – This gene codes for a neural amino acid transporter protein. While studying 15,000 individuals and concluded that non-depressed subjets who possessed the gene exhibited lower expression of the gene in the hippocampus; a region of the brain correlated with major depression. Less of the gene in the hippocampal region of mice were likewise associated with a susceptibility towards chronic stress. Authors believe that the gene expression may interfere with the neuronal circuits implicated in susceptibility to major depression.
The following information on the role of genes in depression is reported by Falk W. Lohoff in his “Overview of the Genetics of Major Depressive Disorder” (2004).
A sample of 656 families revealed links in the following chromosomal regions:
Another study of 784 individuals with MDD-RU (recurring unipolar) found significant linkage signal at:
-Chromosome 12q23 – This chromosomal region has also been correlated with BPD.
Another study found the following correlations:
-Chromosome 18q – This region has also been highly correlated with BPD and anxiety.
A genome-wide linkage scan of 497 sibling pairs found the following correlations:
-Chromosome 12q23-24.11 – 12q is correlated with unipolar depression as well as bipolar disorder.
In another study:
-Chromosome 17 – a region here which includes the SLC6A4 polymorphism, is correlated with MDD, although the researchers do not know exactly which gene or genes in this region are correlated with the disease.
Chromosome 8 – This region has been highly correlated with neuroticism and harm avoidance. No specific genes in the region have yet been identified, although geneticists suspect this region of carrying genes highly associated with these traits.
The authors note that the following two genes have been seen as common
-Serotonin Transporter (5HTT/SLC6A4) – Numerous studies have implicated SLC6A4 in MDD, as well as a 44-bp repeat polymorphism in the promoter region of the gene (5-HTTLPR). It influences levels of expression of the serotonin transporter in vitro.
-Serotonin Receptor 2A (HTR2A) – The authors report a study of those with with a marker in this gene and its value as predictive of the success of treatment with the SSRI citalopram, a significant correlation between symptom improvement when taking the drug and possession of the gene. They report another study in which 760 patients with MDD were treated for 12 weeks with nortriptyline e and escitalopram. The rs9316233 marker in the HTR2A was correlated with 1.1% of response variance, thtey reported.
–SLC6A2 – In the same study, SNPs in this gene, a norepinephrine transporter gene, predicted response to nortryptiline.
–NR3C1 – In the same study, variants in this gene, a glucocorticoid receptor gene, predicted response to both escitalopram and nortryptiline.
BDNF (Brain-Derived Neurotrophic Factor) – This gene is important in neurogenesis, and they report that researchers have correlated levels of this with mood disorders. Lowered levels of this substance in the hiccocampus of animals is correlated with chronic stress. Antidepressants increase the amount of this substance in the hippocampus and also protect against stress-induced decrease. Mood disorders are correlated with loss of hippocampal BDNF as well as loss of the volume in the hippocampus.
Tryptophan hydroxylase (TPH2) – A brain-specific ismorophism of this rate-limiting enzyme has been discovered. It is located on chromosome 12q, which is correlated with BPD. They report that a functional polymorphism (Arg441His) results in the loss of 80% of function in the production of serotonin when expressed in a cell system and that it was a rare mutation unobserved in 219 healthy controls but found in 9 of 87 individuals diagnosed with MDD. Haplotypic associations of sets of markers across this gene, they say, are correlated with positive results, and some variants are predictive of suicidal behavior.
Antisocial Personality Disorder
The relation of the following genes to antisocial personality disorder are discussed in Baker, Bezdjian and Raine (2006):
5-HT1B gene (localized to chromosome 6 in humans) – A 5-HT gene, thus implicating serotonin in aggression. Mice whose 5HT1B gene is removed become extremely aggressive. Those diagnosed with antisocial personality disorder exhibit a reduced variant of a polymorphism or variant of the the 5-HT1B gene.
HTR2A – This gene, according to researchers, is correlated with the amount of money spent on drugs, vandalism, rape, assault hostility, and shoplifting.
HTR1DA – Believed to be involved in 5-Ht metabolism, the C variant of the gene is much more common in adult offenders diagnosed with antisocial personality disorders, as well as children with childhood conduct disorder, than in normal controls.
TDO2 (tryptophan 2,3-dioxydase) – It ought to be kept in mind here that tryptophan is a known precursor to 5-HT. Higher activity of this gene is correlated with lower levels of 5-HT, which is correlated with aggressive behavior. Numerous genetic polymorphisms of the gene are correlated with drug abuse, ADHD, Tourette’s syndrome and alcoholism.
DRD2 gene – correlated with ADHD, addiction, impulse-control problems and problems with compulsion. The Taq A1 allele, a gene variant of DRD2, is correlated with PTSD, alcoholism, drug abuse and conduct disorder.It may also be related to violent behavior, as those who possess it are much more likely to become incarcerated for violent crime as adults, and to engage in fighting behavior in school.
Longer base pairs of the MAOA gene – Correlated with major depression, drug abuse, alcoholism, learning disabilities, ADHD and conduct disorders. Researchers have correlated genetic deficiencies of MAOA with aggression in both humans and mice. MAOA deficiencies in one family sample revealed a null allele at the MAOA locus may be correlated with antisocial behavior in males.
–Oprl1 (Carlson, 2013) – A distinct variation of this gene has been correlated with PTSD in humans. An altered expression of the gene is also correlated with PTSD-like symptoms in experimental mice. The gene exists in amygdala tissue, which is significant, since this part of the brain plays an impotant role in the experience of fear. The mRNA of Oprl1 was downregulated in mice, as opposed to those who had been conditioned to experience fear.
Researchers have been led to believe from these experiments that Oprl1 gene expression influences fear responses and may be correlated with the development of PTSD. There was a specific sequence variation (single-nucleotide polymorphism (SNP)) which seems to have been correlated with PTSD in a group of individuals who had been exposed to traumatic experiences in childhood (Carlson, 2013).
–TPH1 and TPH2 (ULCA, 2012)- These genes control production of serotonin and both may play a role in mediating PTSD. Researchers believe that individuals with these gene variants produce less serotonin, and those who possess specific variants of the genes were more likely to exhibit the symptoms of PTSD.
The following information is taken from “Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies,” published by Marilyn C. Cornelis, Nicole R. Nugent and Karestan C. Koenen.
As of 2010, around 30 studies of genetic predispositions to PTSD had been undertaken. Most genetic variations or “polymorphisms” were either single nucleotide polyporphisms (SNP; in these polymorphisms, a single nucleotide base is different) and variable tandom repeats, or VNTRs. In these, nucleotide sequence repeat pattern is different. 18 of the 30 studies of the genetic predispositions underlying PTSD have focused on genes correlated with serotonergic and dopaminergic systems. Five of these focused on the dopamine receptor
Two of these found a correlation between an SNP called
–TaqIA – This gene exists in the coding region of ankyran repeat and kinase domain which contains one gene, ANKK1, which is located “downstream” of DRD2. A replication of these studies found such a correlation only among a subset of those afflicted with PTSD who were at risk for alcohol abuse.
–rs6277 – This is another DRD2 variant.
-DAT1 – A VNTR in a dopamine transporter gene; correlated with susceptibility to PTSD where there are 9 40-bp repeats.
–D4 (DRD4) – A dopamine receptor correlated with a tendency towards “avoidance/numbing” symptoms of PTSD where the individual is a carrier of the long (7 or 8 repeats) allele.
So much for studies correlating dopaminergic genes with a susceptibility to PTSD. Let us now look at those studies which focused on serotonergic genes and their correlation with susceptibility to PTSD.
There is only one exception to the rule among studies focusing on serotonergic genes, to the tendency to focus on “an insertion/deletion polymorphism in the promoter region of the serotonin transporter (SLC6A4, locus 5-HTTLPR).” The paper reports one study which observed a correlation between s/s genotypes and risk of PTSD. Another study correlated an excessive amount of l/l genotypes with chronic PTSD.
Another study correlated the “s” variant of 5-HTTLPR with a greater risk of PTSD provided there were high degrees of environmental stress, suggesting that there may be a significant element of gene/environment interaction. Yet another study found a correlation between “s” allele carriers who had undergone trauma and the experience of PTSD.
rs6311 – A serotonergic polymorphism; specifically, a G –> A substitution in the serotonin receptor: 2A (5-HT2A). A couple studies found a correlation between the G allele and PTSD.
While dopaminergic and serotonergic factors are commonly implicated in mood disorders, there were some atypical genetic correlations as well. For example, four “highly linked” variants in FKBP5 (FK506 binding protein 5) were correlated with adult PTSD when they occurred in individuals who had been exposed to childhood abuse. One study correlated only one of these variants with PTSD and another correlated 3 of them with PTSD.
Another surprising find was that several variants of GABRA2 (γ-aminobutyric acid A receptor, α2) were correlated with PTSD. The APOE ε2 allele was likewise correlated with a higher tendency among those with PTSD to “re-experience” trauma, and a variant of the regulator of G-protein signaling 2 (RGSW2) was found in one study to be correlated with an elevated risk of exhibiting symptoms of PTSD in high-stress environments.
–RGS2 (Nauert, 2008) – This gene exists on chromosome 1 and codes for a protein with the same name. The protein is important in mediating neurotransmitter receptor activity. These neurotransmitter receptors are the ones targeted by many psychotropic drugs, such as antidepressants and antipsychotics.
Mice whose RGS2 gene is “knocked out” are unusually anxious. In a behavioral and genetic study of 119 families, 9 variations of the gene were associated with “inhibition,” an important personality trait associated with anxiety. Four genetic markers were also correlated with anxiety in a genetic and behavioral study of 700 college students. Genetic variants correlated with inhibition in children were also correlated with introversion, which, as Nauert points out, is associated with social inhibition.
The following potential correlates with anxiety were discussed in “Genetics of Anxiety and Trauma-Related Disorders” by Seth D. Norrholm, PhD and Kerry J. Ressler, MD, PhD.
Seth D. Norrholm, PhD and Kerry J. Ressler, MD, PhD
-5HTTLPR – The S allele of the promoter region of this gene has been correlated with generalized anxiety disorder (GAD).
–MAO-A – This gene polymorphism was more likely to be found in females diagnosed with generalized anxiety disorder (GAD).
These authors believe that genes correlated with major depressive disorder (MDD) will likely be found to correlate with generalized anxiety disorder. These genes include (BDNF), COMT, DAT, FKBP5, and CRHR1.
-Adenosine 2A receptor (ADORA2A)
-serotonin 2A receptor (HTR2A)
-monoamine oxidase A (MAO-A)
Regions on the following chromosomes have been explored for genes correlating with panic disorder:
Chromosome 15q – This gene has been suspected because “it is located near genes coding for GABA-A receptor subunits (e.g., GABRB3, GABRA5). A putative role for these genes in the pathophysiology of panic disorder is supported by previous findings linking these subunits to neuronal inhibitory activity and inhibitory neuronal circuits.”
The following genes have been correlated with social anxiety disorder:
-catechol-O-methyltransferase (COMT) – This gene catabolizes catecholamines.
–SLC6A4 – A serotonin transporter gene. Those with the S variant have higher amygdala activation during stressful public activities, and a higher degree of baseline anxiety. Those with the L allele had higher degrees of adolescent anxiety. The findings have thus been somewhat inconsistent.
The following information on the role of genes in addiction is taken from here:
-A1 allele of D2D2 – A dopamine receptor. More common in cocaine and alcohol addicts.
Mpdz – Mice with this gene exhibit less serious withdrawal symptoms after abruptly ceasing from sedative and hypnotic drugs.
Htr1b – Mice lacking this serotonin receptor gene are more susceptible to cocaine and alcohol addiction.
Cnr1 – Mice without this cannabinoid receptor gene are less prone to morphine addiction.
β2 subunit of nicotinic cholinergic receptors – mice without these receptors are less likely to be addicted to cocaine.
Neuropeptide Y – Mice with less of this are less likely to drink large amounts of alcohol. Those with more of it are more likely to abstain from drinking too much.
Tyramine – Genetically engineered fruit flies who cannot synthesize this are unresponsive to cocaine and are not susceptible to its stimulant effects.
Per2 – Those with a damaged version of this gene drink 3x more alcohol than those with a normal gene.
CYP2A6 – An allelic variant of this gene causes those who smoke to experience nausea and dizziness, which is protective against habitual smoking.
ALDH*2 – Those with two copies of this gene variation are highly unlikely to become alcoholics.
Creb – Mice without this gene are less susceptible to morphine dependence.
Nauert, Rick (2008). Genetic Disposition for Anxiety. Retrieved from: http://psychcentral.com/news/2008/03/04/genetic-disposition-for-anxiety/…
University of Maryland Baltimore. (2009, November 14). Gene knockout may cheer up mice. ScienceDaily. Retrieved June 26, 2014 from www.sciencedaily.com/releases/2009/11/091112191752.htm
Yale University. (2010, October 18). Genetic trigger of depression identified: Potential target for novel class of therapeutic agents. ScienceDaily. Retrieved June 25, 2014 from www.sciencedaily.com/releases/2010/10/101017133639.htm
Cell Press. (2011, May 3). Scientists identify genetic risk for major depression. ScienceDaily. Retrieved June 26, 2014 from www.sciencedaily.com/releases/2011/04/110427131816.htm
Laura A. Baker, Serena Bezdjian, and Adrian Raine. BEHAVIORAL GENETICS: THE SCIENCE OF ANTISOCIAL BEHAVIOR. Law Contemp Probl. 2006; 69(1-2): 7-48. Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174903/
Carlson, Megan (2013). Gene may link to post-traumatic stress disorder, researchers say. Retrieved from; http://news.medill.northwestern.edu/chicago/news.aspx?id=222681
University of California, Los Angeles (UCLA), Health Sciences. (2012, April 2). Genes linked to post-traumatic stress disorder. ScienceDaily. Retrieved May 28, 2014 from www.sciencedaily.com/releases/2012/04/120402093509.htm
Marilyn C. Cornelius, Nicole R. Nugent, and Karestan C. Koenen. Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies. Curr Psychiatry Rep. Aug 2010; 12(4): 313-326.
Seth D. Norrholm, PhD and Kerry J. Ressler, MD, PhD. Genetics of Anxiety and Trauma-Related Disorders. Neuroscience, Nov. 24, 2009; 164(1), 272-287. Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760665/
Falk W. Lohoff. Overview of the Genetics of Major Depressive Disorder. Curr Psychiatry Rep. Dec 2010; 12(6): 539-546.