Psychogenomics: A Literature Review on Genetic

Implications to Abnormal Psychology

Bachelor of Science (Pharmaceutical Science)

Submitted on: 17 June 2016
2264 Words

Loo Zhongde, Joshua

18544967

Introduction
Psychogenomics was a term coined by Nestler in 2001, in how the implications of genetic mutations
relate to dysregulation of protein translation/transcription within the body and its impact on the human
psychology (Nestler, 2001).
Not much progress in the field of psychogenomics was made due to the complexities of the human
genome. Fortunately, the completion of the human genome project in 2003 provided researchers with
many answers regarding gene polymorphisms and how it might be linked to genetic abnormalities.
Coupled with recent advances in molecular biology such as improved next generation sequencing
(NGS) methods like pyrosequencing, scientists are far better equipped to understand the field of
psychogenomics.
Sometimes, it is more convenient to avoid gene sequencing for the detection of the polymorphic
sequence of interest as it is rather time-consuming in a diagnostic context. For example, amplification
of sequences through polymerase chain reaction (PCR) followed by gel electrophoresis can be done to
detect trinucleotide repeat disorders (Goldman, Glei, Lin, & Weinstein, 2010) by comparing it to a
wild type or control. However, sequencing is still crucial as it will help facilitate further understanding
in new polymorphisms.
Single-nucleotide polymorphisms (SNP) and copy number variations (CNV) can be detected through
the use RFLP. SNPs, however, are required to be located on a restriction site to greatly affect fragment
length. SNPs not found at this site will have very little influence on fragment length. In such cases, it
is required to conduct gene sequencing preferably through NGS.
Transcription activator-like effector (TALE) constructs is a recent discovery which helps in the
modification of the genome. This is done by designing TALE to recognise specific sites on the DNA
with an endonuclease attached to cause double-stranded breaks (Mahfouz, et al., 2011). These breaks
will stimulate the bodys repair mechanisms. Researchers can use these TALE constructs to their
advantage through gene expression studies.
Objective
To classify the types of genetic mutations which might result from a polymorphic gene or epigenetic
modifications and how it will lead to abnormal psychological behaviour.
Data Sources
A literature search was done with the terms: psychogenomics, snp gene behaviors,
psychogenomics, Alzheimers in Google Scholar, Science Direct (Elsevier), SCOPUS (Elsevier),
Springer, Wiley Online Library. Findings are limited to after 2009 for relevance. Landmark articles
before 2009 are mentioned to provide further clarification on the articles being discussed.
SNP mutations: Variation in DRD2 dopamine gene predicts extraverted personality (Smillie,
Cooper, Proitsi, Powell, & Pickering, 2010)
In this study, it was hypothesized that a TaqIa polymorphism (rs1800479) have been shown to reduce
the translation of dopamine receptor D2 (DRD2) binding sites (Smillie, Cooper, Proitsi, Powell, &
Pickering, 2010). This polymorphism was not found to be within the promoter regions of the DRD2
gene, or the gene itself but in the ANKK1 gene.
These polymorphisms were detected through the use of a TaqMan quantitative PCR assay. The TaqIa
polymorphic sites are recognised by an oligonucleotide probe, which is attached to a fluorophore and
a quencher. During the PCR procedure, the 5-3 exonuclease activity of Taq polymerase will cleave
the probe. Separation of the fluorophore and quencher will lead to a fluorescence signal which can be
quantified. Increased fluorescence is directly correlated to the presence of the TaqIa polymorphism.

This polymorphism causes a reduction in dopamine binding sites within the mesolimbic pathway.
This is a stimulus resulting in an increase in dopamine production, where it can bind to non-D2
dopaminergic sites. If the dopamine hypothesis is true, the increase of dopamine to other sites will
cause an increase in extraversion in patients with at least one allele of this polymorphism (Smillie,
Cooper, Proitsi, Powell, & Pickering, 2010). However, a study done on Caucasian German adults have
failed to show any correlation (Wacker, Reuter, Hennig, & Stemmler, 2005).
Extraversion as a criterion in measuring the degree of abnormal psychology is difficult as it can be
caused by many confounding factors. Environmental factors can also influence extraversion. An
experiment conducted states that children with the rs1800479 polymorphic trait exhibit extraversion
but it is only seen in parental alcoholism as compared to normal living circumstances (Smillie,
Cooper, Proitsi, Powell, & Pickering, 2010).
The study also mentioned that previous efforts on determining the link between the DRD2 gene and
extraversion were limited due to poor demographic diversity in sample selection (Smillie, Cooper,
Proitsi, Powell, & Pickering, 2010). On the other hand, I believe that this is not an important criterion
in preliminary studies as identification of a causal relationship takes precedence over genetic
diversification within the pool of participants. In fact, polymorphic traits within genomes from
participants of different ethnicities/demographics might add unwanted complexities in establishing a
link between the polymorphic DRD2 and extraversion. For example, possible methylation of DNA
due to environmental exposures might affect behavioural phenotypes.

SNP Mutations: Individual and Additive Effects of the CNRI and FAAH Genes on Brain
Response to Marijuana Cues (Filbey, Schacht, Myers, Chavez, & Hutchison, 2010)
Delta-9-tetrahydrocannabinol (9-THC), the active compound found in marijuana, is not only is able
to simulate the effects of endocannabinoid central cannabinoid receptors (CB1 1) binding but also
reduces inhibition of dopamine (DA) firing within the ventral tegmental area (VTA), a part of the
mesolimbic pathway which is rich in dopamine cell bodies (Filbey, Schacht, Myers, Chavez, &
Hutchison, 2010). This is caused by an effect called the depolarization-induced suppression of
inhibition (Oleson & Cheer, 2012),
The link between cannabinoid and dopamine activity is further substantiated when a CB1 1 receptor
antagonist, SR141716A (Rimonabant) is able to block dopamine firing (Filbey, Schacht, Myers,
Chavez, & Hutchison, 2010). Thus, over stimulation from cannabinoid and dopamine systems can
cause a cannabis dependence (CD), linked to phenotypical traits such as withdrawal and craving.
Genetic polymorphisms can influence the probability of cannabis dependence. The CNR1 and FAAH
polymorphic genes are linked to the increase in CD.
The polymorphisms in CNR1 and FAAH are detected by the TaqMan PCR method.
The CNR1 gene has a SNP (rs202329) from G to A in the third exon. The A allele increases CB 1
receptor translation, leading to increased binding from either endocannabinoids or 9-THC, an
increase in reduced DA firing and subsequently CD rates (Filbey, Schacht, Myers, Chavez, &
Hutchison, 2010). However, no correlation was found in a study done in adolescents (Hartman, et al.,
2009).
The FAAH gene has a missense SNP C385A (rs324420) which causes a reduction in an enzyme
responsible for inactivating N-arachidonoyl-ethanolamine (anandamide), a CB 1 receptor agonist. This
leads to an increase in anandamide binding which similar to the pathway activated by the polymorphic
CNR1 gene, activates both cannabinoid and dopamine pathways (Filbey, Schacht, Myers, Chavez, &

Hutchison, 2010). Again, this was proven in a previous study by (Schacht, Selling, & Hutchison,
2009) where CD effects of the rs324420 genotype are exemplified.
The study employed a bogus pipeline technique, where patients were told that urine analysis would be
conducted for abstinence affirmation, despite that the tests were not sensitive enough to detect
abstinence changes to 9-THC levels (Filbey, Schacht, Myers, Chavez, & Hutchison, 2010). I feel
that this would overall interfere with the reproducibility of this study. Contrary to my opinion, the
author states in a later paper that a bogus pipeline is effective, but only in short abstinence periods
(Filbey & Dunlop, 2014).
CNV Mutations: The Serotonin Transporter Polymorphism (5-HTTLPR): Allelic Variation and
Links with Depressive Symptoms (Goldman, Glei, Lin, & Weinstein, 2010)
Serotonin is a neurotransmitter which is responsible for a wide variety of functions, ranging from
cognitive functions to physical traits such as the ability to affect sleeping patterns. The serotonin
transporter protein (5-HTT) causes a reuptake of serotonin into the synapse, therefore preventing
prolonged effects. A reduction of serotonin reuptake is hypothesized to contribute to depressive
behaviour (Goldman, Glei, Lin, & Weinstein, 2010).
PCR along with gel electrophoresis was used in this experiment for the detection of random fragment
length polymorphisms (RFLP).
Polymorphisms within the regulatory factors for transcription can also cause abnormal
neuropsychology. In this example, the promoter region of the serotonin transporter gene has a
polymorphic mutation (5-HTTLPR) linked to one to two alleles (Goldman, Glei, Lin, & Weinstein,
2010). The mutations present in either a 14-repeat short or a 16-repeat long form. The shorter variant
causes reduced transcription of the SLC6A4 gene, in turn reducing the reuptake of serotonin.
Similarities to a meta-analysis (Risch, et al., 2010) conducted have shown that Asians do have the
short allele variant more frequently as compared to Caucasian participants and that there were links
found between depression risk and genotype polymorphism with consideration of a life stressor.
CpG Methylation: Altered CpG methylation in sporadic Alzheimers disease is associated with
APP and MAPT dysregulation (Iwata, et al., 2014)
Sporadic Alzheimers disease is a condition where most patients will succumb to dementia. Many
hypotheses are present for the disease and this study includes these ideas and will attempt to link them
through possible gene-environment interaction (GxE) due to methylation till its gene expression.
Sporadic Alzheimers disease occurs due to a build-up of amyloid (A) plaques and phosphorylated
tau. As compared to Familial Alzheimers disease (FAD), sporadic Alzheimers disease do not have
any inheritance patterns from genes like amyloid precursor protein (APP), presenilin 1 and 2
(PSEN1)/ (PSEN2). Sporadic Alzheimers disease occurs due to epigenetic changes to the genome.
This two protein accumulation is due to the methylation of the CpG islands in the APP and
microtubule-associated protein tau (MAPT) genes, which leads to an increased expression of both
proteins. However, hypermethylation of GSK3B was hypothesized by the author to contribute to
suppressing gene expression which protects from phosphorylated tau formation in non-neuronal cells.
This hypothesis was supported that neurofibrillary tangles (NFTs) are more often seen in neuronal
cells as compared to glial cells.
In addition to the APP, MAPT and GSK3B gene, the variant genotype 4 for the apolipoprotein E
(APOE) gene causes increased A plaques and phosphorylated tau accumulation as its ability to clear
them away is reduced in comparison to the other genotypes (Iwata, et al., 2014). The risk of sporadic
Alzheimers disease increases but not all carriers of the 4 allele will be affected.

An accumulation of the A plaques and the neurofibrillary tangles is postulated to contribute to the
sporadic Alzheimers disease pathology, affecting neural circuits which overall leads to dementia.
However, scientists are starting to question whether metabolic damages such as oxidative stress might
contribute more to the progression of the disease as compared to directly the toxic effects of A
plaques and the neurofibrillary tangles (Chakrabarti, et al., 2015).
Some techniques that were used in this study was the pyrosequencing method, where it works by a
sequence by synthesis principle. An enzymatic reaction from the procedure will release light which
can help identify the specific nucleotide added and therefore sequenced.
Reverse transcriptase PCR with the use of TaqMan assay was used for quantitative PCR. This was to
monitor gene expression within the normal control and Alzheimers disease.
TALE constructs were used to replicate in vivo CpG methylation of the genes to in vitro experiments.
These TALE constructs were attached to DNMT3a, therefore creating site-specific methylation
mechanisms (Iwata, et al., 2014).
A limitation of the study is that understanding where the sites of CpG methylation is not enough to
link gene mutations to the cognitive phenotypes of Alzheimers disease. The author mentions that
messenger RNA (mRNA) from the post-mortem patients brain are not as stable as compared to DNA.
Furthermore, it is not ethically possible to extract mRNA samples from a living patient. The authors
tried to counteract this issue with the use of TALE constructs to monitor gene expression. Another
possible workaround can be the use of induced pluripotent cells (iPSCs) from sporadic Alzheimers
disease patients to be differentiated to neuronal cells (Hossini, et al., 2015), which could provide
added reliability by using host cells.
Conclusion
The main conundrum in psychogenomics is that abnormal psychology is rarely just caused by
mutation of a single gene, but rather due to the homeostasis disruption within the human body. This
disruption can be seen on many levels, influencing proteomics like in the study done by (Filbey,
Schacht, Myers, Chavez, & Hutchison, 2010), where CNR1 and FAAH mutations can lead to
increased translation of CB1 receptors and agonists respectively and in turn dysregulate dopamine
systems which itself do not have any genetic polymorphisms or also in the study by (Iwata, et al.,
2014), where the presence of these A plaques and neurofibrillary tangles might be secondary to other
effects which might cause dementia and other cognitive abnormalities seen in sporadic Alzheimers
disease.
On a genomic level, abnormal psychology can be indirectly caused by a gene which does not translate
into the protein that is being affected. This is seen in the TaqIa polymorphism (Smillie, Cooper,
Proitsi, Powell, & Pickering, 2010), where a mutation in the ANNK1 gene affects the DRD2 binding
sites. These DRD2 binding sites are translated from the DRD2 gene. Polygenic mutations
Abnormal psychology can also be linked to epigenetic modifications and polygenic mutations.
Sporadic Alzheimers disease can result from methylation of the APP, MAPT, and GSK3B genes. In
addition, carriers of the 4 allele for the APOE gene have an increased risk for the disease.
Developments in the field of psychogenomics are limited by our understanding of the human genome,
despite advancements in sequencing technologies. Also, these psychological abnormalities could be
the result of gene expression patterns that researchers have yet to discover, which are masked and
contribute to chance findings. Solving the missing link between genetics and neuropsychology is a
massive undertaking and only when the mysteries of the human genome is fully known, then, there
will be progress.

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