1. by
Shehab Hassan
Assistant Lecturer of
psychiatry
Supervised by
Prof. Wageeh Abdel Nasser
Professor of Psychiatry
Assiut University
State of the art of
genetics in psychiatry
2. Agenda
Introduction
The Field of Psychiatric Genetics
Study Designs for Genetic Research on Mental Disorders
The concept of Endophenotypes in psychiatry
Epigenetics in psychiatry
Pharmacogenetics
Future directions
2
4. Introduction
In recent years, mental health professionals have
become increasingly aware of the importance of genetic
factors in the etiology of mental disorders. Since the Human
Genome Project began its mapping of the entire sequence of
human DNA in 1990, the implications of its findings for
psychiatric diagnosis and treatment have accumulated
rapidly.
4
5. A new subspecialty known as biological psychiatry (also
called physiological psychology or psychiatric genetics) has
emerged from the discoveries of the last three decades. Biological
psychiatry got its start in the late 1980s, when several research
groups identified genes associated with manic depression and
schizophrenia respectively. These studies ran into difficulties
because of the complexity of the relationship between genetic
factors and mental illness.
5
6. Why complex?
Psychiatric diagnosis relies on a doctor's human judgment and
evaluation of a patient's behavior or appearance.
There is no blood or urine test for schizophrenia.
Diagnostic questionnaires do not have the same degree of precision or
objectivity as laboratory findings.
Mental disorders almost always involve more than one gene.
Studies have shown that one mental disorder can be caused by
different genes on different chromosomes in different populations.
6
7. Genes associated with mental disorders do not always show the
same degree of penetrance , which is defined as the proportion
of individuals carrying a particular variant of a gene (allele or
genotype) that also express an associated trait (phenotype).
Genetic factors in mental disorders interact with a person's
family and cultural environment.
7
9. The Field of Psychiatric Genetics:
The Four Paradigms
Since the early 1980s, several distinct paradigms have
emerged in psychiatric genetics, from different perspectives,
by which investigators have sought to understand the role of
genetic factors in the etiology of psychiatric disorders
(Kendler 2005).
9
10. Paradigm 1:Basic Genetic epidemiology
The goal of basic genetic epidemiology is to quantify the
degree to which individual differences in risk for
developing illness result from familial effects (as assessed
by a family study) or from genetic factors (as determined
by twin or adoption studies) (Busjahn 2002).
10
11. Paradigm 2: Advanced Genetic Epidemiology
The goal of advanced genetic epidemiology is to explore the
nature and mode of action of these genetic risk factors. Some of
the many possible questions that can be asked in advanced genetic
epidemiology are as follows (Kendler, 2001):
1. Are the genetic risk factors specific to a given disorder or shared
with other disorders?
2. Do the genetic risk factors impact on disease risk similarly in
males and females?
11
12. 3. Do the genetic risk factors impact on disease risk by altering the
probability of exposure to environmental risk factors?
5. Does the action of the risk factors change as a function of the
developmental stage of the individual?
6. for disorders with multiple stages (i.e., alcohol consumption must
precede but does not always lead to alcohol dependence), what is
the relationship between the genetic risk factors for these
various stages?
12
13. Paradigm 3: Gene Finding
The goal of gene-finding methods is to determine the
locations in the genome of genes (or more technically, loci) that,
when variation occurs, influence liability for developing psychiatric
disorders.
By examining the distribution of genetic markers within
families or populations, these methods (linkage and/or association)
allow us to infer the probability that a locus in the genomic region
under investigation contributes to disease liability (Kendler 2005).
13
14. Paradigm 4: Molecular Genetics
The goal of the molecular genetic paradigm is to trace
the biological mechanisms by which the DNA variant identified
contributes to the disorder itself.
The first task is to identify the change in gene function and/or expression
resulting from the identified DNA variant.
The subsequent task is to trace, using a range of available methods (e.g.,
molecular, pharmacological, imaging), the etiological pathway(s) from the
DNA variant to the abnormal brain/mind functioning that characterizes the
disorder (Kendler 2005).
14
16. Genetic Models of Familial Transmission
Mendelian Genetic Models:
Assumes that all relevant genetic variation is due to the presence
of alleles at a single locus and that environmental variation is either
irrelevant or unique to an individual.
Diseases transmitted through a single major locus are referred to as
Mendelian diseases, as the pattern of inheritance in families follows
the rules of Mendelian segregation and can usually be recognized
through visual inspection of pedigrees (Robin Marantz, 2009).
16
17. Multilocus Diseases and Complex Inheritance
The general multifactorial model proposes genetic factors that
each make a small relative contribution to the total variance
attributable to genetic factors.
Most mental disorders are presumed to be inherited under such
a polygenic model.
With complex multifactorial inheritance, consideration of
environmental factors becomes a relevant component of
disease models.
17
18. The general complex trait multifactorial model assumes that all
relevant genetic and environmental contributions to variation
can be combined into a normally distributed variable termed
liability.
Familial inheritance is modeled through correlations in liability
between family members, with the following assumptions:
18
19. 1) relevant genes act additively and are each of small effect in
relation to the total variation;
2) environmental contributions are similarly due to many events
whose effects are additive; and
3) there may be multiple thresholds, such that individuals with
scores between threshold values represent milder phenotypic or
“spectrum” cases.
(Balding DJ, 2007)
19
20. Epistasis
epistasis is a phenomenon in which the expression of one
gene depends on the presence of one or more "modifier
genes.“
A gene whose phenotype is expressed is called epistatic,
while one whose phenotype is altered or suppressed is
called hypostatic.
20
21. When multiple genes contribute to risk, the presumption of
additivity (as in the liability-threshold model) serves as a
convenient mathematical baseline but may not at all reflect the
underlying biological reality. Complex interactions among loci of
major or minor effect, termed epistasis, may occur. This refers to
the scenario in which multiple risk alleles combine to confer
greater risk than the additive model would predict.
(Burmeister et al., 2008)
21
23. Study Unit of Analysis Goal
Population Subjects in the general population
Establish lifetime cumulative
incidence
Family Pedigrees
Establish familiarity;
estimate mode of transmission,
risks to relative classes
Twin Monozygotic and dizygotic twins
Distinguish genetic from
environmental effects
Adoption
Adoptees; adoptive and biologic
relatives of adoptees
Distinguish genetic from
environmental effects
Linkage Nuclear and/or extended pedigrees
Establish chromosomal location
of a disease locus
Association
Unrelated affected individuals and
controls
Identify a specific disease locus
Transgenic
Gene expression in model systems
e.g., worm, fly, zebrafish, mouse
Implicate genes, molecules,
pathways, neural circuits
Study Designs for Genetic Research on Mental Disorders
23
24. Family Studies
Family studies for mental and other disorders begin with
affected persons (probands) selected from, for example,
consecutive hospital inpatient admission or a psychiatric case
registry. Available relatives are located and assessed for
psychopathology with structured or semistructured diagnostic
instruments. Recurrence risks are expected to increase as the
degree of relatedness between relatives increases.
24
25. monozygotic twins (zero degree), share 100 percent identical DNA sequence at
the level of their genes.
Full siblings (including DZ twins) and parents and children are first-degree
relatives who share one-half of their genetic material in common.
Second-degree relatives of affected individuals grandparents, grandchildren,
uncles, aunts, nieces, nephews, and half-siblings—share one-quarter of their
genetic material in common.
(Faraone et al., 1999), (Kendler & Prescott, 2006).
25
26. 26
Diagnostic
category
Population
prevelance
Twin
concordance
Heritability
Heritability is the proportion of
variance in familial risk
attributable to genes.
Schizophrenia: 1% MZ: 40–50%;
DZ: 14%
70–85%
Bipolar disorder (BP): 1% MZ: 70%;
DZ: 19%
60–85%
Major depressive
disorder:
5–15% MZ: 46%;
DZ: 20%
40%
Autism and autism
spectrum disorders:
Strict: 0.04%;
spectrum: 0.8%
MZ: 36–82%;
DZ: 6%
90%
Eating disorders: AN: 0.6%; BN 1%;
tenfold more common
in women
MZ: 55% (AN), 23%
(BN);
DZ: 7% (AN), 9% (BN)
AN: 55%;
BN: 60%
Anxiety disorders: All anxiety
disorders:29%
Panic 1–3%
MZ: 23–73%
(panic disorder);
DZ: 0–17%
(panic disorder)
40–50%
(panic disorder)
Obsessive
compulsive
disorder:
1–3% MZ: 50–80%;
DZ: 20–40%
60–70%
28. Twin Studies
Some ways that twins have been used for research purposes
include:
Twins reared-together
Twins reared-apart
The co-twin control method
28
29. 1-The Twin Method (twins reared-together(
The twin method compares the trait resemblance of reared-
together MZ twin pairs (also known as monozygotic, or
identical), who share 100% genetic similarity, versus the
resemblance of reared-together same-sex DZ twin pairs
(also known as dizygotic, or fraternal), who average a 50%
genetic similarity (Joseph, 2004; Plomin et al., 2008).
29
30. 2-Twins Reared-Apart
Reared-apart twin studies have assessed twin resemblance for
psychological traits such as IQ and personality, but have not
assessed twin concordance for psychiatric disorders. This is due
to the difficulty of obtaining a large enough sample of reared-
apart twins to perform such studies (Bouchard et al., 1990).
30
31. 3-co-twin control method.
This method looks at environmental factors that might lead
to different outcomes for twins. For example, researchers
might wish to study the smoking habits of a pair of MZ twins,
one of whom has been diagnosed with lung cancer (Herrell et
al., 1999).
31
32. Adoption Studies
Adoption studies permit the comparison of the effects of
different types of rearing on groups who are assumed to be similar
in their genetic predispositions.
The underlying principle of an adoption study is its assumed
ability to make a clean separation of genetic and environmental
influences, since adoptees inherit the genes of their biological
(birth) parents, but are reared in the environment of another
(adoptive) family with whom they share no genetic relationship
(Jay Joseph, 2006).
32
33. The two most frequently used adoption study models in
psychiatric genetics are the Adoptees method, and the
Adoptees’ Family method.
1-The Adoptees method: begins with parents (usually
mothers) diagnosed with the disorder in question. The
researchers then determine the prevalence of this disorder
among their adopted-away biological offspring (index group).
33
34. The prevalence of the disorder is then compared with that of a
control group consisting of the adopted-away biological offspring
of parents not diagnosed with the disorder. The re-searchers
conclude that a statistically significant higher rate of the
disorder among index versus control adoptees suggests a role
for genetic factors in causing the disorder.
(Rosenthal et al., 1971; Tienariet al., 2003)
34
35. 2-The Adoptees’ Family method begins with adoptees
diagnosed with the disorder in question. A control group of
non-diagnosed adoptees is also established. The investigators
then attempt to identify and diagnose the biological and
adoptive relatives in each group, and make statistical
comparisons between these groups.
35
36. Researchers then compare the diagnostic rates of the
biological versus adoptive relatives of the index adoptee group:
‘‘If the biologic relatives of ill adoptees have higher rates of
illness than the adoptive relatives of ill adoptees, then a genetic
hypothesis is supported.
If the adoptive relatives show higher rates of illness, then an
environmental hypothesis gains support’.
(Faraone & Tsuang, 1995)
36
37. Linkage studies: Establish chromosomal location of
a disease locus
Rest on the principle that large blocks of DNA are inherited
unchanged by meiotic crossover in the offspring. Thus, a
single DNA marker can be used to trace transmission of one of
these blocks from parents to offspring. Linkage studies take
several-hundred polymorphic DNA markers and observe
whether specific parental alleles are inherited within a family
by ill offspring, i.e. the marker alleles co-segregate with
illness within the family.
37
38. If certain markers show this pattern across families more than
would be predicted by chance, the marker is said to show
linkage to the clinical phenotype and presumably to the gene
responsible for it. These markers are usually microsatellites
(regions within DNA where short sequences of nucleotides are
tandemly repeating), but they also may be SNPs. Linkage studies
are usually conducted using the DNA from nuclear and
extended families and measures allele sharing within families.
(Dawn Teare M and Barrett JH, 2005)
38
39. Association Studies: Identify a specific disease
gene locus
association is linkage at very small distance. Association
studies identify whether or not an allele of a marker (or a
few markers) in a small segment of DNA is itself the
disease-causing mutation or is close to it (i.e. in linkage
disequilibrium with it). Association studies accomplish this
by measuring whether a hypothesized disease allele is more
frequent in Unrelated affected individuals relative to the
control population (Kruglyak et al., 2008).
39
40. Candidate gene
The choice of candidates is informed by existing knowledge of
pathways or molecules thought to be involved in a specific disease.
A biological candidate gene might be involved in the
neurotransmitter system that is implicated by the psychoactive drugs
used to treat a disorder (for example, serotonin system genes for
depression).
A positional candidate gene is any gene that maps within a
chromosomal region that is implicated by linkage.
(Alarcon M et al., 2008)
40
42. Endophenotypes
It is a measurable biological (physiological, biochemical,
and anatomical features), behavioral (psychometric pattern) or
cognitive markers that are found more often in individuals with a
disease than in the general population.
The major use of the term was in psychiatric genetics, to
bridge the gap between high-level symptom presentation and low-
level genetic variability, such as single nucleotide polymorphisms.
(Hasler G et al., 2004)
42
43. Some other terms which have a similar meaning but do not
stress the genetic connection as highly are "intermediate
phenotype", "biological marker", "subclinical trait",
"vulnerability marker", and "cognitive marker".
The strength of an endophenotype is its ability to
differentiate between potential diagnoses that present with
similar symptoms.
43
44. Criteria that a biomarker must fulfill to be called
an endophenotype include:
1) The endophenotype is associated with illness in the population.
2) The endophenotype is heritable.
3) The endophenotype is primarily state-independent (manifests in an
individual whether or not illness is active).
4) endophenotype and illness co-segregate Within families,.
5) The endophenotype found in affected family members is found in
nonaffected family members at a higher rate than in the general
population.
(Gershon ES, Goldin LR, 1986 and Gottesman II, Gould TD, 2003) 44
46. Depression
Anhedonia (Impaired Reward Function)
Anhedonia seems to be a relatively specific feature of depression
(Fawcett et al, 1983), and even in patients with schizophrenia,
anhedonia has been related to the depressive syndrome rather than to
the deficit syndrome (Loas et al, 1999).
Associations between dysfunctions of the brain reward system and
anhedonia are the basis of the biological plausibility of anhedonia-
related endophenotypes.
46
47. Epidemiological research provides clues for state-independence,
heritability, and familial association of dysfunctions of the brain
reward system as endophenotype for MDD.
Anhedonia Symptoms Often Precede The Onset Of MDD.
Anhedonia Symptoms Seem To Be Relatively Stable Over Time (Oquendo
Et Al, 2004).
The Associations Between Impairments Of Brain Reward Pathways And
Addiction, Lifetime Comorbidity Of Substance Use Disorders And MDD
(Brook Et Al, 2002) Also Suggest Persistent Familial Abnormalities Of
Brain Reward Pathways In MDD.
47
53. Epigenetics
Epigenetics is the study of changes in gene expression or cellular
phenotype, caused by mechanisms other than changes in the
underlying DNA sequence.
Recent research has demonstrated that complex ‘epigenetic’
mechanisms, which regulate gene activity without altering the
DNA code, have long-lasting effects within mature neurons ((Van
2002).
53
54. Most psychiatric disorders share important features, including
a substantial genetic predisposition and a contribution from
environmental factors.
Recent researches have raised the notion that epigenetic
mechanisms, which exert lasting control over gene expression
without altering the genetic code, could mediate stable
changes in brain function (Jaenisch and Bird 2003).
54
55. Overview of epigenetic mechanisms
The epigenome
Within the nucleus of a cell, the DNA sequence lies
wrapped around histone proteins. The complex of DNA, histones
and non-histone proteins forms a highly condensed structure called
chromatin. The basic unit of chromatin is the nucleosome, which
consists of a histone octamer with a standard length of 147 base
pairs of DNA wound around it. Histone octamer exists of two
copies of each of the core histone proteins H2A, H2B, H3 and H4.
(Jenuwein and Allis 2001)
55
56. The nucleosomal structure and the remodeling
mechanisms of chromatin allows DNA to be accessible to the
transcriptional machinery.
In simplified terms, chromatin exists in:
An inactivated, condensed state, heterochromatin, which does
not allow transcription of genes.
An activated, open state, euchromatin, which allows
individual genes to be transcribed.
56
59. Gene expression
Without altering the genetic code, diversifications in the
patterns of gene expression give rise to differentiating tissues.
Epigenetic mechanisms drive this cellular development and
differentiation, and are therefore at the heart of genetic
expression.
Epigenetic processes activate some genes and inhibit others
and genetic expression becomes increasingly more defined,
restricting the properties of the cell.
59
60. As in other cells, epigenetic mechanisms are essential to the
development of the nervous system. The epigenetic machinery
drives both embryonic and postnatal neural development. It is
involved in neurogenesis (Kuwabara, Hsieh et al. 2004),
neuronal differentiation, cell fate specification (Fan, Beard et
al. 2001) and development of dendrites (Wu, Lessard et al.
2007).
60
61. The course of development of the epigenetic profile is
influenced by environmental factors in utero. In different species
environmental factors such as temperature or the presence of
predators, have been shown to affect the phenotype of the
offspring. In humans and mice, the physiology of the baby is
affected by the nutritional state of the mother. Maternal stress in
rats also alters the phenotype of their offspring (Dolinoy,
Weidman et al. 2007).
61
62. such epigenetic developmental plasticity may involve
preparing the offspring for the type of environment they are
likely to live in (Bateson, Barker et al. 2004). it is now clear that
these mechanisms are dynamically regulated.
Epigenetic remodeling takes place throughout adult life,
under the influence of environmental factors such as nutrition,
drugs, and chemical, physical and psychosocial factors
(Dolinoy, Weidman et al. 2007; Sutherland and Costa 2003).
62
63. In addition, psychiatric disorders such as depression
and schizophrenia appear to be modulated by epigenetic
alterations (Rutten and Mill 2009). Since environmental
factors are known to contribute to these diseases, epigenetic
regulation may be the field where genes and environment
interact, to produce a psychiatric phenotype.
63
64. Epigenetic mechanisms
There are two major types of epigenetic mechanisms that
regulate gene expression in the nervous system.
The first is posttranslational modification of histones.
The second is DNA methylation.
Histone modifications and DNA methylation interact to
modify the structure of the epigenome, determining the
accessibility of DNA to transcription.
(Gibney and Nolan 2010)
64
65. Posttranslational modification of histones:
Posttranslational histone modifications take place at the histone
tail of the nucleosome. The most common are the small covalent
modifications:
Acetylation.
Methylation.
Phosphorylation.
(Tsankova, Renthal et al. 2007)
65
66. 1-Histone acetylation
Histone acetyl transferases (HATs) catalyze the addition of acetyl
groups.
Histone hyperacetylation is associated with decondensation of
chromatin and an increase in gene activity.
Hypoacetylation correlates with repression of chromatin and a
decrease in gene activity. The balance between the opposing
activity of HATs and HDACs on histone tails, is an important factor
in regulating transcription (Sleiman, Basso et al. 2009).
66
67. Defects in this interplay can lead to neurodegenerative diseases.
Restraint stress
Induces decreased levels of total BDNF mRNA in the
hippocampus and decreased acetylation at histone H3 at the
BDNF gene, associated with reduced levels of BDNF protein
(Angelucci, Brene et al. 2005).
67
68. Elevated HDAC1 expression levels are detected in the
prefrontal cortices of schizophrenia subjects. The mRNA
levels of glutamic acid decarboxylase (GAD) show a strong
and negative correlation with the mRNA levels of HDAC1,
HDAC3 and HDAC4 (Sharma, Grayson et al. 2008).
68
69. 2-Histone methylation
Interestingly, methylation of different lysine residues can
achieve opposite effects on gene activity; it can cause both
repression and activation depending on which lysine residue
of the histone tail is methylated. In psychiatric epigenetics,
focus lies on methylation of histone H3. (Mosammaparast
and Shi 2010).
69
70. 3-Histone phosphorylation
several nuclear protein kinases and protein phosphatases are
known that add or remove phosphate groups from the histone tail.
The protein kinase MSK 1 (mitogen- and stress-activated protein
kinase) and the protein phosphatase inhibitor DARPP-32
(dopamine and cAMP-regulated phosphoprotein) have been
shown to regulate phosphorylation in the brain.
Phosphorylation of histones is associated with the promotion of
transcriptional activity. (Renthal and Nestler 2009).
70
71. Stress induces phosphoacetylation at the BDNF gene in
the hippocampus. This is regulated by the GABAA and the
NMDA receptor, as drugs that target these strongly affect levels
of phosphoacetylation, suggesting that GABA and glutamate
can set intracellular mechanisms into action to alter BDNF-
associated chromatin (Chandramohan et al. 2010)
71
72. DNA methylation
It is catalyzed by DNA methyltransferases (DNMT)
DNA methylation is associated with transcriptional repression,
and this process is enhanced by methyl-binding proteins. These
proteins bind specifically to methylated DNA, and further
repress genetic transcription by recruiting chromatin-remodeling
complexes. (Gibney and Nolan 2010)
72
73. The synthesis of catecholamines is mediated by the Catechol-O
methyl transferase (COMT) enzyme, and the COMT gene has often
been associated with schizophrenia. COMT has two isoforms
encoded by the same gene:
Membrane Bound (MB)-COMT, mainly expressed in the brain.
Soluble (S)-COMT, which is predominantly expressed in
peripheral cells.
73
74. MB-COMT promoter DNA is frequently hypomethylated in
schizophrenia and bipolar disorder patients, particularly in the
left frontal lobe. This corresponds with an increase in transcript
levels of MB-COMT in both schizophrenia and bipolar disorder
patients, and a decrease in expression of the dopamine
receptor gene DRD1 (Abdolmaleky, Cheng et al. 2006).
74
75. Genomic imprinting
For most genes, we inherit two working copies one from mother
and one from father. But with imprinted genes, we inherit only
one working copy.
Depending on the gene, either the copy from mom or the copy
from dad is epigenetically silenced.
Silencing usually happens through the DNA methylation during
egg or sperm formation. (Goos LM, Ragsdale G. 2008)
75
79. Pharmacogenetics
Pharmacogenetic studies are driven by several distinct motivations:
1) pharmacogenetic influences on differential treatment response can help
clinicians use appropriately targeted treatments for specific individuals;
2) determining predictors of adverse effects can help clinicians’ to avoid
treatments for specific individuals;
3) deepening our understanding of how treatments work can assist with the
discovery of new targets for treatment development;
4) predicting metabolic profiles can help with medication or dosage choices.
(Apud et al., 2012)
79
81. Pharmacogenetics represent the variability in drug response and
metabolism due to genetic variant. The overall aim of
Pharmacogenetics is to contribute to drug choice and dosage according
to the individual genetic makeup, thus leading to a personalized, more
efficacious, and less harmful therapy (Klotz, U. 2007)
So, Treatment according to pharmacogenetics
Right Drug
Right Dose
Right Patient
81
82. Pharmacogenomics: is the technology that analyzes how the genetic
makeup of an individual affects his/her response to drugs.
It combines the knowledge of pharmacology and of genomics.
It is the technology that deals with the influence of genetic variation on
drug response in patients by correlating gene expression with a drug's
efficacy or toxicity.
Pharmacogenomics aims to develop rational means to optimize drug
therapy, with respect to the patients' genotype, to ensure maximum
efficacy with minimal adverse effects.(wang l , 2000).
82
84. According to study in this April, 2001 Nature Genetics. Up
to 70 percent of the population may have a genetic
abnormality that causes them to metabolize many of the
drugs on the market particularly slowly-meaning that
chemicals hang around in the body longer and have more
time to toxic effects.
84
85. Pharmacogenetics Individualized drug therapies:
Genes affected the way drugs are handled in the body
>2 million people hospitalized in one year (1994 ) because of
reactions to properly prescribed drug
There is currently a great effort to define gene sequence
differences (SNPs) that influence drug metabolism.
There are about 3 million single base difference in DNA
sequence between any two people –SNPs
85
86. What does this mean for medication?
Opportunity!
To understand how single genes influence health, disease
and response to treatment
To understand how groups of genes work together to
influence patient outcomes
To understand how to optimize treatment for every patient
86
87. Most Psychotropic Medications are metabolized by the
p450 Enzymes
True of all common SSRI’s.
True of common tricycles antidepressants.
True of some benzodiazepines and antipsychotic.
87
88. Polymorphic Drug-Metabolizing Enzymes
More than 50 CYP genes, about 10 of them are of major
importance in psychiatry each is coded for by a specific
gene.eg.: (CYP 3A, CYP 2D6, CYP2C19, CYP1A2, CYP2C9, )
There is extensive variability in allele distribution of some of
these genes. (Nelson D, 2003)
There is considerable variability in the distribution of these
polymorphisms across different ethnic groups.
88
89. CYP2D6 and CYP2C19 belong to the Cytochrome P450 oxidase
family.
CYP2D6 has over 100 variants, 2C19 has mainly three.
They are responsible for the majority of the inter-individual
variability in the ability to metabolize drugs.
89
90. Key polymorphisms of these genes are associated with variability in
the Effectiveness of metabolism and the four phenotypes of
CYP2D6:
Poor Metabolizers (PM)
Intermediate Metabolizers (IM)
Extensive Metabolizers, Those with normal function (EM)
Ultrarapid Metabolizers (URM)
90
91. For CYP2C19, there are only two phenotypes: PM and EM.
If a substrate of the enzyme is given to the patient as a
medication, and if the patient has reduced CYP2D6 or
CYP2C19 activity, the patient will have elevated drug
concentration in their body, and therefore severe side effects
may occur. On the other hand, for the UM patient, the drug
concentration might be too low to have a therapeutic effect.
91
92. Genetic basis of variability
The genetic basis for extensive and poor metaboliser
variability is the CYP2D6 allele, located on chromosome 22.
Subjects possessing certain allelic variants will show normal,
decreased, or no CYP2D6 function, depending on the allele.
92
94. Ethnic factors in variability
Ethnicity is a factor in the occurrence of CYP2D6
variability.
The prevalence of CYP2D6 poor metabolizers is
approximately 6–10% in white populations, as they have
the non-functional CYP2D6*4 allele.
but is lower in most other ethnic groups such as Asians
(2%).
94
95. 50% of Asians possess the CYP2D6*10 allele, which produces
decreased CYP2D6 function as intermediate metabolisers.
In blacks, the frequency of poor metabolizers is greater than
for whites.
The occurrence of CYP2D6 ultrarapid metabolisers appears to
be greater among Middle Eastern and North African
populations.
95
96. Poor Metabolizers
Poor Metabolizer (PM) range in severity and can result in a
serious inability to clear medications that can result in serious
side effects.
Intermediate Metabolizers
Some have fairly adequate capacity to produce sufficient
enzymes while others are more vulnerable. Inhibition by other
medications in intermediate metabolizers is a more serious
concern.
96
97. Extensive Metabolizer
(EM) are “normal”. Molecular biologists refer to them as
“wild types”. In most Caucasian population they are in fact the
most common genotype. Current dosing schedules assume that
the patient is an extensive metabolizer.
Ultrarapid Metabolizers
(URM) rapidly clear medication and can minimize or
eliminate the therapeutic response.
97
98. 2D6
A critical enzyme for fluoxetine, paroxetine and the tricyclic
antidepressants .
A highly variable gene with more than 100 identified
polymorphisms.
Located at a chromosomal site on chromosome 22 where
crossovers occur frequently.
98
99. Dextropmethorphan is Metabolized by 2D6
Dextromethorphan clearance has been used as a pharmacokinetic
assay to identify 2D6 metabolic variation.
Dextromethorphan abuse in poor metabolizers is more likely lead
to psychiatric symptoms including psychosis.
2D6 Is Inhibited By:
Fluoxetine
Paroxetine
Haloperidol
99
102. AmpliChip CYP450 Test is a clinical test from Roche. The
test aims to find the specific gene types (a genotype) of the patient
that will determine how he or she metabolizes certain medicines,
therefore guides the doctors to prescribe medicine for best
effectiveness and least side effects.
The AmpliChip CYP450 Test determines the genotype of
the patient in terms of two cytochrome P450 enzymes: 2D6 and
2C19.
102
103. With the recent FDA clearance of the AmpliChipCYP450
Test, physicians can, for the time, base their dose and drug
selection on scientific criteria, with data obtained from a
small blood sample.
Instead of relying on lengthy trial-and error approaches for
optimizing first drug therapy, physicians may achieve
earlier success using their patient's metabolic profile as a
guide to dosing.
103
105. 1-Use of Endophenotypes for Classification
There is abundant research on comorbidity, dimensional
classification of disorders, and inclusion of subthreshold
diagnostic categories and diagnostic spectra in the DSM-V. As
this effort continues, research on the classification of the
phenotype for genetic and other biologic studies should
increasingly strive for classification that may more closely
represent expression of underlying biologic systems.
105
106. Endophenotypes, as it give more direct expressions of
underlying genes and the broader disease phenotype, will help
to unravel the complexity of transmission of the mental
disorders.
Progress in understanding and identification of endophenotypes
may bridge the gap between the genetic and biological factors
and the manifest phenotypes of mental illness
106
107. 2-Genotyping
Genotyping of the cytochrome P-450 2D6 gene is the first
pharmacogenomic test to be widely used. It is available to
practicing clinicians at the Mayo clinic Medical Laboratories.
Mayo Medical Laboratories has expanded its capabilities to
include pharmacogenomic tests for the cytochrome P-450
2C19 gene, the cytochrome P-450 2C9 gene, the serotonin
transporter gene (SLC6A4), and two of the serotonin receptor
genes (2A and 2C).
107
108. Indications for 2D6 Genotyping
To identify ultra-rapid metabolizers of these same
medications. If a patient metabolizes a drug too quickly,
the drug doesn’t have the intended effect.
Poor 2D6 metabolizers are believed to be at increased risk
for manic or hypomanic symptoms.
Poor 2D6 metabolizers are more susceptible to sexual
dysfunction and are at increased risk for the development
of common side effects such as headaches and diarrhea.
108
109. Children are more vulnerable to the side effects of
medications than adults because their complaints are often
taken less seriously. By testing children, physicians can
help them avoid adverse reactions.
Pharmacogenomic testing is particularly indicated for
children whose mother or father has been shown to be
either a poor or ultra-rapid 2D6 metabolizer
109
110. Older patients also may benefit from pharmacogenetic testing:
They may not remember which medications they have taken.
Whether they suffered side effects from those medications.
Whether they responded well to them.
Geriatric patients often take many medications and may be at risk for
drug interactions. for patients who are poor metabolizers, these
interactions can be dangerous.
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111. 3-Gene Therapy
A functioning gene is introduced into the patient’s cell
aiming to correct an inborn genetic error, or introduce a
new function in the cell.
Leading to permanent genetic alteration of cells.
Produce definite alteration of genotype and phenotype.
111
112. Application in psychiatry
The transplanted neural progenitor cells engineered to over
express and secretes NGF into the nucleus basalis of middle-
aged rats. Remarkably, led to enhanced spatial learning in old
age in these animals.
Over expression of the dopamine signal transduction molecule
CREB (by means of microinjection of a herpes simplex virus 1
vector into the nucleus accumbens) decreased the reward
properties of cocaine (Carlezon et al., 2000).
CREB (cAMP response element-binding protein) is a cellular transcription factor. 112
113. Difficulties
there are some big hurdles to overcome before such techniques can
be routinely used in patients, and especially in patients with
psychiatric disorders:
we have all the neurons we are ever going to have by age 4 or 5,
and that ends up being a huge limitation in gene therapy for the
simple reason that almost all gene therapy techniques used are built
around the need of cells still dividing, replicating their DNA,
because that is the point where you slip in the novel DNA.
113
114. there are no ways to get therapeutic genes and their transporters
into the human brain without injecting them through the skull.
If such material is injected into the bloodstream or
cerebrospinal fluid, it cannot cross the brain’s blood-brain
barrier to get inside the brain. The same holds true for material
inhaled through the nose.
114
115. gene therapy is not capable of exerting such long-term effects
at this point in its development. for instance, unless gene
therapy is given to a rat within four hours of having a stroke, it
does not work.
several genes may play a part in turning other genes on and off.
for example, certain genes work together to stimulate cell
division and growth, but if these are not regulated, the inserted
genes could cause tumor formation and cancer.
115
116. viral vectors must be carefully controlled lest they infect the
patient with a viral disease. Some vectors, like retroviruses,
also can enter cells functioning properly and interfere with the
natural biological processes, possibly leading to other diseases.
Other viral vectors, like the adenoviruses, often are recognized
and destroyed by the immune system so their therapeutic
effects are short-lived.
116
117. 4-HDAC inhibitors
HDAC inhibitors might function as antidepressants, or effectively
enhance the action of existing antidepressants.
The tricyclic antidepressant imipramine increases histone
acetylation at specific promoters of the gene encoding BDNF, in
part by reducing levels of HDAC.
increasing histone acetylation within the hippocampus may
reverse the social avoidance observed in mice subjected to chronic
stress.
117
118. valproic acid (VPA) is commonly used in the treatment of
epilepsy and bipolar disorder. It increases GABAergic
activity by inhibiting GABA transaminase. Moreover, VPA is
a potent HDAC inhibitor of class I and II HDACs and the
most extensively investigated inhibitor in psychiatric
epigenetics.
118
119. 5-DNMT inhibitors
Some evidence indicates that DNMT inhibitors may be useful in
psychiatric therapy. compounds 5-aza-dC (AZA), zebularine and
doxorubicin inhibit DNMT1 and DNMT3 and decrease DNA
methylation of the reelin promoter in neural progenitor cells. This
dramatically increases reelin and GAD67 mRNA levels, showing
that the expression of the reelin and GAD67 genes is mediated by
DNMTs. DNMT3 (Tian, Hu et al. 2009).
119
