Psychiatric genetics:

principles and applications

Ravi Philip Rajkumar

Department of Psychiatry,
NIMHANS, Bangalore
 Introduction
• The exact aetiology of most psychiatric
disorders is unknown.
• However, there is a growing body of evidence
that points towards biological as well as
environmental factors.
• The two are not mutually exclusive, but their
contributions vary in individual cases.
• Biological contributions to illness may be
“hard-wired” and have a genetic component.
 Introduction
• Psychiatric disorders are broad entities, unlikely
to have a single genetic cause.
• Various methods exist to determine:
1. does a disorder run in families?
2. if it does, is this due to genes or
environment?
3. if it is due to genes, how much do they
contribute vs. environmental factors?
4. what are the genes involved?
 Topics in psychiatric genetics
• Underlying concepts
• Technical aspects
• Study principles and methods
• Findings in individual disorders
• Limitations and controversies
• Zeroing in: endophenotypes
• Predicting response: pharmacogenomics
• What we know: genetic counselling
 I. Underlying concepts
• The biopsychosocial hypothesis
• Gene – environment interaction
• Mendelian genetics and beyond
• Genetic models
 The biopsychosocial hypothesis
PSYCHOLOGICAL
FACTORS
Traits, coping,
defences.....

BIOLOGICAL
CONTRIBUTION
MENTAL
Often genetically
ILLNESS
related

ENVIRONMENTAL
FACTORS
Family, social,
cultural, substances,
adverse life events
 Gene-environment interaction
• The relationship between genes and
environment is non-linear.
• Often, it is the interaction of one or more
genetic vulnerabilities with environmental
factors that determines illness.
• In other words, both are necessary, but may
not be sufficient to produce the illness.
 Gene-environment interaction:
an example (Caspi et al., 2003)

GENETIC CODE
Polymorphism of LIFE STRESSORS
the serotonin Adverse life events
transporter in early life
(5-HTT)

DEPRESSION
in adult life
 Gene-environment interaction:
a more complex example
PERSONALITY
schizotypal,
“schizotaxia”

GENETIC CODE
“SELF- FIRST-
Family history of
MEDICATION?” EPISODE
schizophrenia
(Gene – COMT? NR1? PSYCHOSIS
CHRNA7? CNR1?)
CANNABIS
USE
 Other examples
• HPA axis genes and stress in alcoholism – acts
as a maintaining factor and cause for relapse
• The dopamine D2 receptor and serotonin
transporter genes in PTSD – associated with
vulnerability
• Monoamine oxidase A (MAOA) genes and early
life adversity – associated with adult antisocial
behaviour
 Mendelian genetics
• More applicable to single-gene disorders
• Principles of dominant and recessive genes
• Alleles of a gene
• Genotype and phenotype
• Principle of segregation
• Principle of independent assortment
• Commonly applied in neuropsychiatric
disorders
 Mendelian disorders in psychiatry
• Autosomal dominant • Autosomal recessive

Huntington's disease Wilson's disease

Familial Alzheimer's Lysosomal disorders
Phenylketonuria
 Later modifications of Mendel's
concepts
• Linkage
• Co-dominance
• Penetrance
• Epistasis
• Hardy-Weinberg equilibrium
• Trinucleotide repeats and anticipation
• Epigenetics and imprinting
 Linkage
• As per Mendel's principles, genes are inherited
independently (one by one) and not in blocks.
• However, it has been found that certain traits
may be inherited together and not show
independent assortment.
• This is due to their proximity on the relevant
segment of the chromosome.
• This phenomenon is called linkage.
 Linkage disequilbrium
• We do not know which genes cause psychiatric
disorders.
• Instead, we use markers spaced evenly along
the genotype to localize them.
• These markers may be:
Restriction fragment length polymorphisms
Single nucleotide polymorphisms
 Linkage disequilbrium
• Markers that are close to a possible disease
gene will be inherited along with it – they show
linkage
• This implies that if the frequency of a particular
marker is higher in affected subjects than
controls, a disease gene may be close to it.
• This phenomenon is called linkage
dysequilbrium, because in a normal population,
we would expect equal frequencies.
 Co-dominance
• In Mendel's model, genes exist as dominant
and recessive forms or alleles
• However, other models exist wherein both
genes may both be expressed equally, or at
least concurrently.
• This phenomenon is known as co-dominance: a
common example would be the ABO blood
group genes.
 Penetrance
• In Mendel's model, a gene either manifests as a
given phenotype (1) or not (0).
• However, some autosomal dominant human
disorders show marked variance in phenotype,
even when the same gene is present.
• This is known as penetrance, and can confound
genetic studies by obscuring the pattern of
inheritance.
 Epistasis
• Sometimes, more than one gene may be
required for a given phenotype.
• These two genes are at different loci.
• Their effects are interactive, but not additive.
• In other words, genes A and B at different loci
lead to phenotype C; neither A nor B alone lead
to C.
• This is known as gene-gene interaction, or
epistasis.
 Hardy-Weinberg equilibrium
• Suppose that two alleles P and Q of a gene
exist, and their relative frequencies in a
population are p and q.
• The sum of p and q is 1.
• It can be shown that the frequency of
genotypes in the population would be
p2 + 2pq + q2
• This is known as Hardy-Weinberg equilibrium.
 An example
• Consider a gene M for musical talent.
• Form p (more talent) is present in 60% (0.6) of
a given population. P and Q are co-dominant.
• q = 1 – p = 0.4
• If Hardy-Weinberg equilibrium holds, the
frequencies would be:
pp : 0.36 (0.6 x 0.6) – very talented
pq : 0.48 (2 x 0.6 x 0.4) – fair talent
qq : 0.16 (0.4 x 0.4) – least talent
Assumptions in the Hardy-Weinberg
equilibrium
• Mating is random – if good musicians (pp) selectively
marry good musicians (pp), this assumption does not
hold.
• There is no selection – if good musicians have a
shorter life span or reduced reproductive capacity, pp
would be selected out.
• There is no emigration – if poor musicians migrate to
the U.S., the frequency of qq in India would fall
• There are no mutations (for example, creating a new
allele r that confers more talent)
 Trinucleotide repeats
• Certain genes are noticed to contain repeating
sequences of trinucleotide bases, such as CAG
or CGG.
• The number of these repeats affects the
functioning of the gene and may lead to
disease.
• These disorders are known as trinucleotide
repeat disorders.
 Examples of trinucleotide repeat
disorders
• Huntington's disease – CAG repeats in the
huntingtin gene on chromosome 4.
• Spinocerebellar ataxia – CAG repeats on
various chromosomes (6, 12, 16)
• Fragile X syndrome – CGG repeats on the long
arm of chromosome X.
• ? Schizophrenia – one genetic model of
schizophrenia involves CAG repeats at 6p, 8p
and 22q, and perhaps other areas
 Numbers and severity
• The number of repeats often correlates with
the phenotype.
• For example, in Huntington's disease, clinical
symptoms usually appear when there are >38
CAG repeats.
• In Fragile X syndrome, <43 CGG repeats are
normal, 43-200 are carriers, and >200 have the
clinical syndrome.
 Anticipation
• When a trinucleotide repeat disease gene is
transmitted to offspring, the number of repeats
may undergo expansion.
• This may be related to the origin of the gene –
in Huntington's, paternal genes are more likely
to expand.
• This leads to offspring developing the illness at
an earlier age and with greater severity; this
process is known as anticipation.
 Epigenetics
• Thus far, we have considered the DNA
sequence of genes as being of prime
importance.
• However, genes in DNA exist in chromosomes,
associated with proteins (histones).
• The chemical structure of DNA can undergo
modifications, such as methylation,
phosphorylation, acetylation, etc....
• The amino acids of histones can also undergo
such modifications.
 Epigenetics
• These changes do not alter the sequence of
nucleotides in genes.
• However, they may affect the activation and
level of expression of the respective genes.
• These processes are collectively called
epigenetic modifications, and share certain
interesting properties
 Epigenetics .vs. “classical” genetics
• Maintained in somatic cell replication
• May be maintained during meiosis, or
modified, or completely removed
• Subject to random or stochatic effects
• Modifiable by environmental factors, such as
nutrition, substances or hormones
• Modifications (epimutations) may “regress to
the mean” with age
 An epigenetic model of
schizophrenia (Petronis, 2004)
 Phenomena that may be explained
by epigenetics in psychosis
• Familial and sporadic cases
• Discordance in monozygotic twins
• Course and resolution of the illness
• Effects of gender
• Persistence of the illness despite evolutionary
disadvantages
• Non-replicability of “classical” studies
• Anticipation and parent-of-origin effects
 Imprinting
• Paternal and maternal copies of the same gene
undergo epigenetic modifications.
• This process is called imprinting, and leads to
differential expression of genes in the offspring
depending on which copy is inherited.
• This can lead to differences in illness expression
– e.g. Prader-Willi and Angelman syndromes
have the same genetic mutation, but different
symptoms
 Genetic models
• Mendelian
• Mendelian with variable penetrance
• Mendelian with imprinting
• Oligogenic – a small number of key genes
interacting
• Mixed – a single major gene + oligogenes
• Polygenic – multiple genes of small effect
 The general genetic model
• Vp = Vg + Vc + Ve

where Vp = total variation in a phenotype

Vg = genetic effect
Vc = common environmental effect
Ve = nonshared environmental
effect
(including error)

The V values refer to variances.

 Further divisions
• The genetic contribution, Vg, can be further
written as

Vg = Va + Vd

where Va = additive genetic effects

Vd = dominance effects
 Heritability
• Heritability is defined as the proportion of the
total phenotypic variance explained by genetic
factors.

h = Vg / Vp

• This can be further subdivided into broad- and

narrow-sense heritability.
 Two measures of heritability
• Narrow-sense heritability – the proportion of
total phenotypic variance explained by additive
genes, or Va / Vp.

• Broad-sense heritability – the proportion of

genetic variance explained by the total genetic
variance; calculated as above.
 Techniques utilized in genetic
studies
• Cleavage of DNA at specific sites by restriction
endonucleases
• Using markers – RFLPs, SNPs, trinucleotide
repeats
• Hybridization of markers and complementary
sequences – fluorescent, immune, etc.
• Karotyping and other cytogenetic methods
• Examining sequences of DNA that have been
conserved evolutionarily, or haplotypes
 Techniques utilized in genetic
studies
• The polymerase chain reaction – using
bacterial DNA polymerase to amplify sequences
• Recombinant DNA technology to examine
gene expression and products
• Knock-out and transgenic animal models to
study the effects of a single gene or gene
product
 Techniques utilized in genetic
studies
• Using the map of the human genome from the
Human Genome Project
• Micro-array techniques, which use
semiconductor techniques or robotics to
amplify and examine markers, and to measure
mRNA levels
• Postmortem studies on human brains
• Newer statistical methods - bio-informatics
 Classical psychiatric genetics
DOES THE DISORDER RUN IN FAMILIES?
Family studies – establish familiality

IS FAMILIALITY DUE TO GENES OR THE ENVIRONMENT?

Twin studies – examine concordance rates in twin pairs

HOW MUCH DO GENES AND THE ENVIRONMENT CONTRIBUTE?

Adoption studies – separate genetic and environmental contributions

WHICH GENES ARE INVOLVED?

Linkage and association studies

HOW DO THE GENES PRODUCE THE DISEASE?

Molecular genetics
 More recent concepts
• Endophenotype approaches

• Animal models – knockout mice, etc.

• Pharmacogenetics and pharmacogenomics

 The first step: family studies
• Family studies establish that a given disorder
runs in families.
• However, they do not directly show whether
this is due to genes or environmental factors.
• In family studies, affective individuals
(probands) are selected, and their families are
examined for a given disorder.
• Their rates of the disorder are then compared
with either a control group or the population.
 Two types of family studies
• Family history method: the proband is
interviewed, and information about mental
illness in relatives is collected. Simpler, but less
reliable; underestimates true rates.

• Family study method: all available relatives are

interviewed directly. Time-consuming, but
more reliable.
 Genetic distance
• Family studies cannot directly give estimates of
genetic contributions.
• However, if the rate of disorders falls as the
amount of shared DNA between relatives
decreases (increased genetic distance), a
genetic component is likely.
 An example
• A family study of OCD found rates of 7% in first-
degree relatives, and 2% in second-degree
relatives.
• The population rate is 2-3%.
• This suggests that:
1. OCD is familial.
2. a genetic contribution is likely.
 Twin studies
• Monozygotic (MZ) twins share 100% genetic
material, while dizygotic (DZ) twins share as
much as brothers or sisters (50%)
• Concordance is defined as the possibility that
both members of a twin pair will have the
disorder being studied.
• It is assumed that MZ and DZ twins grow up in
similar environments (the “equal-environment
assumption”)
 Twin studies
• If a disorder is determined by environmental
factors, concordance rates in MZ and DZ twins
should be similar.
• On the other hand, if it is genetically
determined, concordance should be more in
MZ than in DZ twins.
• The extent of concordance provides an
estimate of the genetic contribution.
 An example
• A study finds that the concordance for bipolar
disorder in MZ twins is 60%, and in DZ twins
20%
• This indicates that genetic factors are likely
more important (numerically) than
environmental factors in bipolar disorder.
• However, the <100% concordance indicates
that there is still a 40% contribution from
environmental factors.
 Adoption studies
• Adoption studies broadly seek to determine
whether heredity (nature) or environment
(nurture) are more important in a given
disorder.
• They rely on the assumption of “no selective
placement” - that is, that the environment
provided by adoptive parents is only randomly
similar to that of the biological parents.
 Adoption studies
• Consider two groups of adopted children,
named A and B.(CROSS FOSTERING)
• Group A are children of patients with a given
disorder (say depression).
• Group B are children whose adoptive parents
have the given disorder, or controls.
• We now compare the rates of depression in
groups A and B, as well as the agreement
between their diagnoses and those of
biological and adopted parents.
 Adoption studies
• In our example, group A have a (presumed)
genetic liability to depression, but no
environmental loading.
• The opposite holds good for group B.
• Measuring the rates of the disorder in groups
would give us a measure of whether
environmental or genetic vulnerability plays a
greater role.
 An example
• A study is done examining 50 children of
alcoholics who are adopted, and 50 children
whose adoptive parents have alcoholism.
• The study finds that rates of alcoholism are 12%
in the first group, and 6% in the second group.
• The greater agreement with the biological
parents' diagnosis points to a genetic
component.
 Finding the genes
• Once the familiality and genetic component of
a given disorder are established, the gene or
genes responsible must be identified.
• This is done by means of four methods:
1. Linkage analysis
2. Association analysis
3. Candidate gene analysis
4. Cytogenetic analysis
 Linkage studies
• These studies exploit the phenomenon of
linkage described earlier.
• Either a few families with high illness density or
more families with affected sibling pairs can be
chosen.
• In this method, genetic markers or
polymorphisms spaced evenly around the
genome are used.
 Linkage studies
• There are two types of linkage studies:

Parametric (family method)

Non-parametric (affected sibling pair or ASP

method)
 Parametric linkage studies
• The frequency of illness, and a particular
marker or markers, are measured in families.
• A predetermined measure of inheritance is
chosen.
• The likelihood of there being linkage with the
disease is divided by the likelihood of no
linkage (odds score).
• The logarithm of this score is taken.
 The LOD score
• This score is known as the logarithm of the
odds ratio, or LOD score.
• Roughly, a LOD of 3 establishes linkage, and a
LOD of -2 excludes it.
• A high LOD score indicates a high probability of
a disease gene being in linkage with the marker.
• Most linkage studies are based on variants of
Mendelian models; results in psychiatric
disorders have been conflicting.
 Nonparametric linkage studies
• Also known as the affected sibling pair (ASP)
method
• In this disorder, the frequency with which the
given genetic marker is inherited from a parent
is measured.
• If this frequency exceeds 50% in affected pairs
of siblings, linkage is likely (i.e. the disease gene
and the inherited marker are in linkage.)
 Association studies
• Simpler than linkage studies.
• In this method, the frequency of markers is
compared in affected and unaffected subjects.
• A chi-square test is used to compare
frequencies of the marker in both groups, and
the relative risk can be calculated.
• In such studies, populations must ideally be as
genetically homogeneous as possible.
 How do we find the genes once
linkage is established?
• Use a candidate approach – that is, concentrate
on those markers close to genes that may be
relevant.
• If these are not known, systematically search
the region close to the marker.
• Ideally, an entire genome scan for linkage
disequilibrium should be done – this is time-
consuming, but modern technologies help.
 Candidate gene studies
• In these studies, genes that code for proteins
believed to be important in a given disorder are
studied in affected and unaffected patients.
• Since the pathophysiology of psychiatric illness
is not generally known, these genes have to be
“guessed at” - e.g dopamine receptors in
schizophrenia.
• Comparing frequencies of different gene
polymorphisms may show associations
between a gene and a given disorder.
 Cytogenetic studies
• These are used when disorders in chromosome
number or structure are suspected.
• They are more useful in studying inherited
neuropsychiatric syndromes where aneuploidy
or structural deficits are diagnostic
• Examples: Down's syndrome, Turner's
syndrome, fragile X syndrome
 Findings in common disorders
• Schizophrenia
• Bipolar disorder
• Depression
• OCD
• Panic disorder
• Alcohol dependence syndrome
Genetic contributions across
disorders
(Merikangas and Risch, 2003)
Heritability estimates for common
disorders
(Hill and Sahhar, 2006)
Schizophrenia
 Schizophrenia
• Family studies have found high odds ratios for
affected relatives, up to 9-14.
• Rates are higher in first than in second degree
relatives, and approach population rates for
third degree relatives.
• Familiality seems to be stronger in the case of
early onset schizophrenia (defined as <25 years
in genetic studies)
 Schizophrenia
• Concordance for monozygotic twins is 47-53%,
as opposed to around 4-15% for dizygotic twins
• Risk of schizophrenia in the offspring of
unaffected twins is equal to that in the
offspring of affected twins.
• Rates of schizoaffective disorder and other
nonaffective psychoses are also higher in twins.
 Schizophrenia
• Adoption studies have shown closer
concordance for biological than adoptive
parents and relatives.
• There is some evidence for shared genetic
liability to schizophrenia and bipolar disorder
(common linkages at 6q, 10q, 13q and 22q)
• There is also a link with psychotic mood
disorders and personality disorders, especially
Cluster A personality.
 Genes implicated in schizophrenia
• Catechol O-methyl transferase (COMT) – 22q
• Proline dehydrogenase (PRODH) – 22q
• Neuregulin (NRG1) – 8p
• Calcineurin A gamma (PPP3CC) – 8p
• Dystrobrevin binding protein – 6p
• DAAO and G72 – epistasis – 13q
• Cholinergic alpha-7 receptor – 15q
• Dopamine beta-hydroxylase and NMDA
receptor subunit - 9q
 Bipolar disorder
• Family studies find an odds ratio of 5-10 for
first-degree relatives.
• This effect is stronger for early-onset bipolar
disorder.
• Monozygotic twin concordance is 67%, and
dizygotic twin concordance is 20%
• Two adoption studies found higher rates in
biological parents, and normal rates in adoptive
parents.
 Bipolar disorder
• Link to unipolar depression in one direction –
bipolar probands have more relatives with
unipolar disorder, but not vice versa.
• Significant association with substance use
disorders and conduct disorders in family
studies.
• Linkage with schizophrenia / schizoaffective as
discussed above.
 Genes in bipolar disorder
• Brain-derived neurotrophic factor (BDNF) – 11p
• G-protein receptor kinase (GSK-3) – 22q
• G72 (modulates NMDA receptors) – 13q
• Others – GSK-3 beta, Clock genes
 Depression
• Risk elevated by 15-25% in relatives of affected
probands, compared to controls.
• Familiality is strongest for early onset
depression, and absent in late-life depression.
• Comorbid anxiety and alcoholism may also
predict greater familiality.
• Twin studies generally have found similar
concordance in mono- and dizygotic twins.
 Depression
• Heritability in twins may be more in women
and in early-onset depression.
• Adoption studies using narrow definitions did
not find much higher rates in biological
relatives, while a study using a broad definition
did so.
• There is an association between depression and
panic disorder, as well as alcoholism, in
families.
 Depression
• Winokur proposed the concept of the
depressive spectrum, including alcoholism,
antisocial behaviour and somatization /
conversion.
• On the whole, the heritability of depression is
lower than that of BPAD.
• BPAD probands have more relatives with
unipolar depression than controls.
 Genes in depression
• Few identified:

1. BDNF on 11p
2. Cyclic AMP response element binding protein
(CREB) on chromosome 2
3. Serotonin transporter (5HTT) polymorphism -
17q
4. Monoamine oxidase A - Xp
 OCD
• Family studies – elevated risk in first-, but not
second-degree relatives.
• Higher familality in juvenile OCD (onset <18
years)
• Twin studies found concordance only for
broadly defined OC symptoms, but not OCD.
• High rates of tic disorder (14%) in first-degree
relatives of OCD probands
 OCD
• OCD probands also show elevated rates of
Tourette's syndrome (2-5%; population 0.03-
0.4%) in first-degree relatives.
• Some evidence for a shared basis with major
depression.
• Studies of 5HTT polymorphisms – inconsistent
results
• An animal model recently identified a neuronal
scaffolding protein (Sapap-3) that may play a
role in OCD.
 Panic disorder
• Familiality shown in family studies, more in the
case of female relatives.
• Some genetic overlap with generalized anxiety
disorder and major depression.
• 2-3 fold higher concordance in monozygotic
twins compared to dizygotic twins
• Significant overlap with alcohol dependence in
first-degree relatives, more so in women with
panic disorder.
 Alcoholism
• Early-onset alcoholism (<25 years, Type II) has a
strong genetic component.
• Association with externalizing disorders and
adult antisocial behaviour.
• Association with mood disorders, both unipolar
and bipolar.
• Twin and adoption studies support a genetic
aetiology for alcoholism, especially in men.
 Alcoholism
• There may be an interaction between genotype
and gender – women require more loading
• Polygenic models have the best support.
• Linkage to chromosomes 1, 7 and 2.
• Possible protective effect of alcohol
dehydrogenase on chromosome 4
• Serotonin, GABA-A and dopamine receptor
genes also implicated
 Limitations of genetic studies in
psychiatry
• Diagnoses are heterogenous, and do not match
to clear phenotypes
• Reliability / validity in identifying cases
• The problem of “broad definitions”
• Genetic heterogeneity and phenocopies
• Simplifying assumptions
• Effect of population interbreeding, migration
• Methodological issues and flaws
 Limitations of genetic studies in
psychiatry
• Complex genetics – not fitting into simple
models
• Genetic pleiotropy – one gene manifesting in
different ways
• Other effects, such as epigenetic modification
• Statistical errors due to multiple comparisons
 Phenocopies
Learning
ADHD
disability

PERVASIVE
HYPERACT
Conduct IVITY Developmental
disorder
disorders
(phenotype
)

Anxiety disorder Abuse and PTSD

 Controversies
• “Genetic determinism”
• Past horrors, such as the eugenics movement
• Stigmatization?
• Negative emotions in patients and relatives
• Fatalism, poor coping, nonadherence
• Ethical issues – disclosing risk
• Unscrupulous marketing
• Ownership of genetic material
 Overcoming hurdles
• One way of avoiding these problems is in
identifying a “purer” and more valid and
reliable phenotype.
• Ideally, it should be measurable by a laboratory
test or other objective procedure.
• This “intermediate phenotype” approach gave
rise to the concept of endophenotypes.
 The endophenotype concept
5HTTLPR TEST
FINDI
NG STRESS
MAOA
DEPRESSIO
N
BDNF
TEST
FINDI
PROTECTIVE
NG FACTOR
CREB

“INTERMEDIATE CLINICAL
GENES PHENOTYPES” DISORDER
 Definition
• Endophenotypes are “internal phenotypes”
discoverable by a laboratory test.
• They interact with environmental factors to
produce a complex phenotype, or disorder.
• Because of their greater simplicity, validity and
reliability, it is easier to study them in families
and associate them with candidate genes.
 Criteria for an endophenotype
• Associated with the illness in the population.
• Heritable.
• State-independent (a “trait marker”)
• Co-segregate with the illness in families.
• Found more frequently in unaffected relatives
than in the general population.
 Types of endophenotype
• Structural anatomical
• Functional neuroanatomical
• Physical finding
• Biochemical
• Neuroendocrine
• Neuropsychological
 Examples of endophenotypes
• Sensory gating anomalies in schizophrenia.
• Eye tracking abnormalities in schizophrenia.
• Neuropsychological deficits in bipolar disorder,
schizophrenia and possibly OCD.
 Pharmacogenetics and
pharmacogenomics
• Though effective drugs exist for many
psychiatric disorders, they are not curative.
• Their exact mechanisms of action are unclear.
• Response rates are generally around 50-60%.
• Attempts to predict response based on clinical
parameters are not always successful.
 Evolution of the concept
• Initially, attention was devoted to identifying
genetic differences in drug metabolism.
• Later, this generalized to finding genes that
could be associated with drug response, or with
specific adverse effects.
• The latest advance has been genome scanning
to identify the effects of drugs on gene
expression and protein synthesis
 Difference between the two terms
• Pharmacogenetics: examines the effect of
single genes on a drug – either kinetically or
dynamically.

• Pharmacogenomics: correlating actual levels of

gene expression or polymorphisms with drug
effects.
 Examples of pharmacogenetic
findings:
• Nonresponse to SSRIs is associated with
metabotropic glutamate receptor
polymorphisms (STAR*D report finding)
• Association of 5HT-2C variations with clozapine-
induced weight gain
• Association between 5HTTLPR polymorphisms
and SSRI response
 Examples of pharmacogenetic
findings
• Heritability of response to SSRIs and MAOIs
• Association between a 5HT-2A (C102/C102)
variant and response to clozapine and
risperidone
• Linkage of lithium response to markers on
chromosomes 15 and 7
• D3 receptor variants and susceptibility to
tardive dyskinesia
 Genetic counseling
• “The process of helping persons understand
and adapt to the medical, psychological and
familial implications of genetic contributions to
disease”
- National Society of Genetic Counselors
• Has to be non-directive and encourage patient
autonomy
 Steps
• Information gathering

• Information provision

• Support
 Information gathering
• Establishment of rapport

• Identifying the client's needs

• Identifying the disease

• Family history
 Information provision
• Details about aetiology

• Providing gene-environment models

• Explaining recurrence risk

• Explaining effect of lifestyle and environmental

factors
 Support
• Aiding decision making

• Reducing risk behaviours

• Strenghtening coping

• Reducing stigma and negative attitudes

• Support to parents and caregivers

 Who should receive genetic
counseling?
• Affected individuals planning families

• Affected individuals with risk factors /

behaviours

• Siblings of affected individuals

• Parents of affected individuals