Schizophrenia

and
Genetics

Presented by:

CHARLINE A. RADISLAO
Introduction
 Symptoms

• The symptomsof schizophrenia can be categorized

into three wide-ranging groups.
1. Positive symptoms
2. Negative symptoms
3. Cognitive symptoms
 Symptoms

• Positive symptoms include: hallucinations

(visual and auditory), delusions, and racing
thoughts.
• Negative symptoms include: apathy, lack of
emotion, and poor social functioning.
• Cognitive symptoms include: disorganized
thoughts, difficulty concentrating or
completing tasks, and memory problems.
Positive and Negative Symptoms

Negative Positive
A logia (abnormal speech) Hallucinations
Lack of interest in life Delusions
Poor in making decisions Bizarre behavior
Languages impairment Unusual thoughts

Social isolation Disorder of movement

 Causes

• No one knows the exact causes of Schizophrenia, but

multiple possible factors have beendiscovered.
• These factors include:
1. Genetics
2. Brain chemical imbalance
3. Environmental factors
4. Family history
 Etiology of Schizophrenia
• The etiology(causes) and pathogenesis of
schizophrenia is not known

• It is accepted, that schizophrenia is „the

group of schizophrenias“ which origin is
multifactorial:
– internal factors : genetic, inborn, biochemical
– external factors : trauma, infection of CNS,
stress
 Etiologic pathway
Genetic predisposition

Early environmental insults

Neurodevelopmental abnormalities and target features

Later environmental insults

Further brain dysfunction and schizophrenia

psychosis

Neurodegeneration and schizophrenia

 Epidemiology

Affects 1 % of the general population.

8% in siblings of affected subjects.
12% in offsprings of one affected parent.
40% in offsprings of two affected parents.
47% in subjects of affected monozygotic twins.
Genetics of Scizophrenia
 What is known about the inheritance pattern of
schizophrenia?
• Although results from family, twin, and adoption studies provide
overwhelming evidence that genetic factors play a part in the cause of
schizophrenia, the exact mechanisms of genetic transmission remain
unidentified.

• Despite the genetic and phenotypic complexity of schizophrenia, much

progress has been made.

• Research has largely excluded the possibility that genes of major effect
exist; linkage analysis has provided independently replicated evidence for
genes of moderate effect on several chromosomal regions.

• Association studies suggest that alleles of at least two genes, those

encoding D3 and 5HT 2A, confer a small rise in susceptibility to
schizophrenia, and there are convergent findings from several different
lines of research implicating regions such as 22q11, although no specific
causative genes for schizophrenia have been definitively identified yet.
 What genetic testing could you offer this
couple?
• Predictive genetic testing is unlikely to be useful in the
near future except for some rare pedigrees if a single
major locus is identified.
• One area where genetic testing may be more helpful,
however, is schizophrenia associated with VCFS.
• In most cases, the deletion of 22q11 occurs as a de novo
mutation, but in 10% of those affected, it is inherited from
a parent, who may have a mild presentation of the
syndrome .
• In such cases, parents could be tested for the deletion,
and, if confirmed, testing could be offered to siblings,
especially if other clinical features are present.
Twin, adoption and family studies
Twin, adoption and family studies
 Family Studies
• As can be seen from the graph below, schizophrenia definitely has a very
significant genetic component.

• Those who have a third degree relative with schizophrenia are twice as
likely to develop schizophrenia as those in the general population.

• Those with a second degree relative have a several-fold higher incidence of

schizophrenia than the general population, and first degree relatives have
an incidence of schizophrenia an order of magnitude higher than the
general populace.

• Following are two images that summarize the average risks for developing
schizophrenia for different groups of people.
• (The statistics in the two images vary slightly due to inclusion of different
study data).
family studies
family studies
Risk of Developing Schizophrenia (in percents) from
SCHIZOPHRENIA GENESIS
family studies
Genome-wide studies
Genome-wide studies
new findings promise new insights
 If we were to summarize all of these data on an ideogram of the human
genome, they might look like this; to the right of the chromosome is an "S" for
schizophrenia susceptibility, a "B" for bipolar, and an asterisk (*) where both
types of disorders are mapped to the same location.
Candidate gene studies: gene studied
Candidate gene studies: gene studied
Brain-derived neurotrophic(BDNF) gene
Brain-derived neurotrophic(BDNF) gene
Brain-derived neurotrophic(BDNF) gene
Brain-derived neurotrophic(BDNF) gene
Brain-derived neurotrophic(BDNF) gene
Brain-derived neurotrophic(BDNF) gene
Epidermal growth factor(EGF)gene
Epidermal growth factor(EGF)gene
Epidermal growth factor(EGF)gene
Epidermal growth factor(EGF)gene
NOTCH4 gene
NOTCH4 gene
NOTCH4 gene
NOTCH4 gene
NOTCH4 gene
NOTCH4 gene
Catechol-o-methyltransferase(COMT) gene
Catechol-o-methyltransferase(COMT) gene
Catechol-o-methyltransferase(COMT) gene
Apolipoprotein E(APOE) gene
Apolipoprotein E(APOE) gene
Apolipoprotein E(APOE) gene
Apolipoprotein E(APOE) gene
Apolipoprotein E(APOE) gene
 Genetics of Scizophrenia :DNA
variation
• Evidence for a substantial genetic contribution comes from family, twin and
adoption studies but the underlying causes and pathogenesis of the
disorder remains unknown.

• The past few years have witnessed marked progress in our understanding
of genetic risk at the level of DNA variation, which has been largely driven
by applying advanced genomic technologies to very large samples.

• There is evidence that risk variants occur across the full allelic frequency
spectrum, many of which are associated with other neuropsychiatric
disorders.

• Moreover, genetic associations involving different classes of mutations have

now implicated specific biological pathways in disease pathogenesis.
recent advances in schizophrenia genetics

• de novo mutation,

• rare copy number variation (CNV),

• rare single nucleotide variant (SNV, defined as point

mutations with a frequency less than 1%)

• and small insertion/deletion (indel) mutations

• and single nucleotide polymorphisms (SNPs, defined as

point mutations with a frequency greater than 1%)
Schizophrenia risk alleles
Copy number variations implicated in schizophrenia
 Brain chemical imbalance:
• Abnormal production or reaction to the important
chemical neurotransmitter dopamine and maybe
others.

• Dopamine is responsible in sending messages

through the brain and effects how the brain
perceives things.

• Imbalance between dopamine and serotonin.

HYPOTHE
SIS
Lets remind ourselves how
neurotransmitters work
 DOPAMINE HYPOTHESIS

The Dopamine hypothesis states that the

brain of schizophrenic patients produces
more dopamine than normal brains.

–Evidence comes from

–studies with drugs
–post mortems
–pet scans
 Normal Level of Elevated Level of
Dopamine I n The Dopamine In The Brain of
Human Brain a Schizophrenic Patient
(specifically the D2
receptor)

 Neurons that use the transmitter ‘dopamine’ fire too often and transmit
too many messages or toooften.
 Certain D2 receptors are known to play a key role in guidingattention.
 Lowering DA activity helps remove the symptoms ofschizophrenia
Etiology of Schizophrenia - Neurodevelopment
Model
• Neurodevelopmental model supposes in
schizophrenia the presence of “silent lesion” in the
brain, mostly in the parts, important for the
development of integration (frontal, parietal and
temporal), which is caused by different factors
(genetic, inborn, infection, trauma...) during very
early development of the brain in prenatal or early
postnatal period of life.
 Environmental factors

• Stress inducing environmental factors such as

social pressure, physical or sexual abuse, loss of
loved ones, hormones, malnutrition, and early
exposure to viruses.

• The major brain changes that occur during

puberty has also been identified as a possible
contributing factor.
 TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies
Gene SNP Identifiers Associated (p<0.01) With at
Least One Endophenotype in
Current Study
ADRBK2a rs576895, rs558934, rs5761116
AKT1a rs2494732, rs1130214 rs2494732b
BDNF rs6265
CACNG2a rs2267341, rs2283981,
rs738518
CHRNA7 rs3087454
COMTa rs737865, rs4680
DAOa rs2070587, rs3741775
DAOAa rs1341402, rs239119, rs778294
DGCR2a rs2072123, rs807759
DISC1 rs3738401, rs2793092, rs821597b, rs843979
rs2793091, rs2492367,
rs1000731, rs821597,
rs4658971, rs843979, rs821616
 TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies
Gene SNP Identifiers Associated (p<0.01) With at Least
One Endophenotype in Current
Study
DRD3a rs2134655, rs963468, rs6280
DTNBP1a rs1040410, rs760666, rs2619539,
rs3213207, rs1011313, rs2619528,
rs2619522, rs1018381, rs909706
ERBB4a rs7598440
GABRB2a rs187269, rs252944, rs194072,
rs1816072, rs1816071
GAD1a rs2241165, rs3791850
GRID1a rs2814351
GRIK3 rs3767045
GRIK4a rs948028, rs2852217, rs879602, rs948028
rs1954787, rs4935752, rs6589846,
rs433110, rs7111184, rs2156635,
rs949054
GRIN1a rs11146020 rs11146020b
GRIN2Ba rs1805502, rs890, rs1805247,
rs1806201, rs7301328
GRM3a rs6465084, rs2237562, rs1468412
HTR2A rs7333412, rs2296972, rs659734, rs6313b
rs6313
 TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies
Gene SNP Identifiers Associated (p<0.01) With at Least
One Endophenotype in Current
Study

HTR7a rs12412496
NCAM1 rs1943620, rs1836796, rs1821693,
rs646558, rs2303377
NEUROG1a rs2344485, rs2344484
NOTCH4a rs422951, rs520692, rs915894
PPP1R1Ba rs4795390, rs879606, rs907094,
rs3764352
RGS4a rs2661319, rs2842030
SLC18A1 rs1390938, rs2270637, rs2270641, rs17092104b
rs17092104
SLC6A3a rs11564773, rs6876225, rs2550936, rs11564773b, rs11564758b
rs6347, rs11564759, rs11564758,
rs2963238

SP4 rs11974306, rs12668354, rs12668354b

rs12673091
TAAR6a rs8192625, rs4305745, rs6903874
ZDHHC8a rs175174
 Is Schizophrenia Genetic?
• Not entirely: there are certain genes that
contribute, but onset depends on the environment
around the individual.

• The only gene strongly connected to

schizophrenia is a gene on chromosome
22 named COMT. When abnormal, COMT
depletes the frontal lobes in the brain of
the neurochemical dopamine, causing
hallucinations and an impaired sense of
reality, both symptoms of schizophrenia.
 Can Schizophrenia Be Inherited?
• No, not specifically. There is one gene linked to
the disorder; however, little heredity is found in
schizophrenia.

• The highest instance of there being

two cases of schizophrenia in a family is
between twins, and the instance of that is
less than 50%, suggesting that
schizophrenia is not inherited. Again, it
depends on the environment around the
individual.
“ I f you talk to God,

you are praying;

if God talks to you,

you have schizophrenia”

“Human beings are ultimately
nothing but carriers-passageways-
for genes.
They ride us into the ground like
racehorses from generation to
generation. Genes don't think about
what constitutes good or evil.
They don't care whether we are happy or
unhappy. We're just means to an end for them.
The only thing they think about is what is
most efficient for them.”
Haruki Murakami, 1Q84