DYSLEXIA

Phenotype
• Evolution - speech developed (started with a verbal relay of knowledge, we then had too
much knowledge – had to record it) – however the genes needed were already
established, they just needed to be modified
• Reading & writing - cultural innovations - learned behaviour
• Individuals with dyslexia find it difficult to acquire and consolidate written information
• Not mental retardation
• People with dyslexia show normal performance with regard to other cognitive functions,
and have normal or higher than normal intelligence
• Heritability = 40 – 70 %
• Memory formation is intact – accessing the memories is the problem
• Most problems have to do with defects in cell migration, cell adhesion and axon growth
– ability of neurons to communicate with eachother – neurons have different functions
in different areas and the areas need to communicate with eachother to make sense of
written words

How will I test it?

• Reading and writing comprehensions

Quantitative studies
• Twin studies:
MZ:55–70%
• Family studies:
About 40% of siblings of children with dyslexia might have the same reading issues.
Up to 49% of parents of kids with dyslexia may have it too.
Overall motor dexterity correlate with reading ability
• Adoption studies:
Kids who are adopted are twice as likely to have learning and attention issues as kids
who aren’t adopted.

How will I test it?

Family and twin studies are a very effective way to study dyslexia; I would therefore do a
combined family and twin quantitative study using families with one or more twin sets over
various generations to study dyslexia. These families would also have to have a history of
dyslexia. Various written and vocal tests would then need to be performed in order to
determine the phonological awareness and phonological decoding abilities of the various
members of the population. I would choose these two phenotypes specifically as they are
viewed as the most influential on dyslexia. The advantages of combined family and twin studies
is the fact that one is able to track the possible alleles through generations and make
deductions from that. Disadvantages include the fact that it is difficult to find families large
enough to study these days. Also the fact that candidate genes may be specific to specific
families within a population, and therefore may be difficult to replicate.

Molecular studies

• DYX1C1
 Dyslexia-susceptibility-1,candidate-1.
The result of a rare chromosomal translocation, involving chromosomes 2 and 15. There
are also 2 rare SNPs found in higher frequency in individuals suffering from dyslexia. This
was all found in a Finnish population, derived from a small founder population, making
them genetically more homogeneous than other population, explaining why this
couldn’t be replicated in other populations.
• KIAA0319
On chromosome 6. This was found in 2 populations: a British population (Berkshire), and
an American population (Colorado). The complication around this gene is its connection
to another gene (adjacent to it), also connected to dyslexia – the DCDC2 gene.
• DCDC2
Associated with brain disorders resulting from deficits in neuronal tandem repeat
sequences in an intron. Associations were found between the short tandem repeats and
dyslexia. It was later proven in a linkage study in a German population to be a candidate
gene.
• ROBO1
The discovery of this candidate gene came from 2 interesting cases:
A large Finnish family, consisting of 4 generations and 74 members, of which 27 were
dyslexic, showed a simple single dominant gene linked to a region on chromosome 3.
Another translocation was implicated between chromosome 3 and chromosome 8. This
translocation pinned the phenotype down to a disruption in ROBO1. It appears that the
reduction in expression of this gene during development of the nervous system
predisposes to dyslexia.

How will I test it? : (Discuss the one you choose – including advantages & disadvantages)
Linkage studies

It is evident that there are multiple molecular agents that predispose an individual to
dyslexia, I would therefore choose to focus on the agent that has the least data on it to
study. In this case it would be the EKN1 gene on chromosome 15, due to the fact that the
actual function of the gene is relatively unknown. As mentioned above, I would conduct an
association mapping study to determine if any there were any single nucleotide
polymorphisms or other mutations at any specific loci on the EKN1 gene played a significant
role on the development of dyslexia. This would be done by sequencing the EKN1 gene of all
the individuals in the family and examining them for any significant differences between the
individuals diagnosed with dyslexia, and those not. Should there be any significant findings,
the study would need to be repeated on a larger scale to ensure the results are valid. This
test needs to be done in a homogenous population.

Ethical considerations
• Consent – children, parents, schools, board of education in province you are conducting
study in
• Children may be ostracized or bullied by other children if they know they may have
dyslexia
• Parents – environmental influence
• Lack of proper identification

What do I have to take into account?

• Which sequence variants are actually associated
• How predictive are the alleles for the manifestation of the disorder – can we really
screen a baby and make a conclusion that it’ll be dyslexic
• Do the genes only function during development or do they function in adult brain – if the
gene is only disrupted during development, if we replace the faulty protein will the
child have normal development? Or is this something that is stable throughout life?
• What other genes interact with the candidate gene? – are there signs of penetrance and
epistasis?
ADDICTION
Phenotype

• Chronic course - periods of abstinence and relapse (even long abstinence periods)
• Vulnerability to relapse à long-lasting / permanent neurobiological changes
• Tremendous individual differences to vulnerability à many experience and never use
compulsively
• Substance abuse accounts for more deaths, illnesses and disabilities than any other
preventable health condition
• Long-term exposure = physiological & behavioural changes
- Tolerance - need to increase dosage
- Sensitization - enhancement of drug response due to repeated use
- Dependence - adapted physiological state - develops to compensate for excessive
stimulation by drug
- Withdrawal syndrome - somatic, affective and motivational components - unmasking of
adapted state

Driving forces

• Incentive-sensitization theory of addiction

– Sensitization occurs in neural systems that attribute incentive salience to drugs & their
cue’s
• Drug ‘wanting’ sensitizes; drug ‘liking’ shows tolerance
• Addiction - cycle of hedonic dysregulation driven by many factors; important role of
negative affective states that occur with abstinence
• Role of learning - drugs facilitate some; trigger neuroadaptation seen in learning
• Not mutually exclusive - different factors, different times

The phenotype is only expressed when an individual who is genetically predisposed to the
addiction trait, is exposed to the drug and uses it. This is a characteristic of a gene-by-
environment interaction, where specific environmental factors must interact with the
specific genotype for a specific phenotype/behaviour to develop. Common physiological
changes of an addict: Over time, continuous exposure to drugs can result in physical,
functional changes in specific neuropathways in the brain, strengthening the synapses in
that specific pathway. Drugs also change one’s normal state of homeostasis, to compensate
for physiological changes made by the drug. This results in dependency of drugs.Different
drugs have different initial targets in the brain. Most drugs stimulate dopaminergic neurons
in the brain. Dopamine neurotransmitter plays a role in reward (the associated “high”) and
motivation, which explains the urge to consume more drugs, resulting in addiction.

How will I test it?

• Does the individual show dependence on the substance?

• Does the individual experience withdrawal if they do not consume the substance?

Quantitative studies
To investigate whether addiction is a heritable trait, the best study design to use is twin study
design. Twin study designs are based on “equal environment assumption”. In twin study design,
the presence of a shared trait, in this case addiction, in both members of a pair of twins will be
observed. In other words the concordance rate of monozygotic twins to that of dizygotic twins
will be compared.
Findings suggest that addiction could be a heritable trait with possible genetic influences.
Although, the genotype is sensitive to environmental influence.
A disadvantage of the twin study design is that epigenetics can change expressions of genes in
twins. The addiction phenotype will not be expressed if twins are not exposed to drugs, even if
the twins are genetically predisposed. Although twin study design is based on the “equal
environment assumption”, environmental conditions for monozygotic twins may be different.

Molecular studies
• Amphetamines – dopamine pathway
• Methamphetamines – dopamine and serotonin pathway
• Ecstasy – serotonin pathway
• Marijuana – dopamine pathway
• Nicotine – acetylcholine pathway
• Alcohol – dopamine and NE pathways

How would I test it?

In order to understand the genetic basis of addiction, it is vital to link the variation in the
addiction phenotype to genes that cause the trait. This is done by identifying and mapping
quantitative trait loci (QTL)..The loci identified are independent of one another and each locus
contributes to the trait. Initially, linkage mapping could be performed. This involves mapping
QTLs in families or inbreed lines. The advantage of using linkage mapping is to exclude
unwanted DNA variation. One would have to find families (preferably large families) who are
willing to participate in the experiment. Specifically families which contain members who are
addicted to non-illicit drugs, such as alcohol or nicotine would have to be looked for. Thereafter
the genomes of all the members in a family would have to be sequenced the genomes of all the
addicts and non-addicts would have to be compared. The moment differences in the genomes
that the addicts share, and of which the non-addicts don’t have, are detected, then I have found
a QTL. To exactly identify the candidate gene (QTL) or to link the gene to a specific marker,
interval mapping analysis would have to be performed. Interval mapping involves scanning the
genome for QTLs which lie within the interval between two adjacent markers.

Ethical considerations
Ethical considerations for this study would be to treat all participants equally and fairly. The
information that they provide will be kept completely confidential. The participants will also not
be harmed during the study and all samples taken from participants will be done safely and
professionally. The participants who take part in the study should want to find help with their
addiction. The participants must understand that the purpose of the study is to understand
more about addiction and what can be done from a genetic aspect in order to treat it.
ALZHEIMERS
Phenotype
• Progressive neurodegenerative disease
• Global cognitive decline – starts in one area and spreads
• Accumulation of β-amyloid deposits (fatty deposits – accumulate on axons – obstruction
of signal conduction – action potential cant move – can’t access memories) and
neurofibrillary tangles in the brain (plaques and tangles)
• Stutter – cant find correct words
• Do everything slower – forget how to do things
• Forget people, forget what they’re doing
• Risk = old age and family history
• Early onset
- <5% of cases
- onset before 60
- rare and highly penetrant
- autosomal dominant inheritance
• Late onset
- >65 years
- majority of cases
- no Mendelian inheritance
- increased risk from common polymorphisms with low penetrance but high prevalence

How will I test this?

Genetic screening can be done early on for Alzheimer’s candidate genes. This can be done by
sequencing the individual’s genome and looking for any potential markers.

Quantitative studies
Family studies are a good way to study Alzheimer’s as it allows one to track the familial
tendency of an individual developing Alzheimer’s. Family studies also allow for the trait to be
completely quantified, allowing for the exclusion of all possible variation that does not result
from genetics ie. Environmental factors. Family studies are especially convenient when studying
early onset Alzheimer’s as it shows an autosomal dominant pattern of inheritance. One is then
able to track specific candidate genes through generations that may be linked with early onset
Alzheimer’s. This can lead to early diagnosis and for preventative measures to be put in place.
Disadvantages of family studies include the fact that it is difficult to find families large enough to
study these days. Also the fact that candidate genes may be unique to specific families within a
population as a result of possible inbreeding, this may make studies difficult to replicate.

Molecular studies
Early onset
• PSEN1
- screen for this during genetic screening
- more than 200 mutations
- onset in late 40’s
- 3 genes share biochemical pathway – encode for Aβ42 species – leads to neuronal cell
death
 - mutation creates non-amyloidogenic soluble APPα fragment – build up of this causes
plaques and tangles
• Other = PSEN2 and APP
Late onset
• APOE
- screen for this during genetic screening
- role in cholesterol transport and lipid metabolism
- 4 alleles (E1, E2, E3, E4)
- E4 shows comorbidity with familial hypercholoestolemia – increase in cholesterol levels
– cant remove it – plaques and tangles form
- E1 linked to longevity
• Other = BIN1, CD33, CLU, CR1, PICALM

How will I test this?

Linkage studies can be done on the candidate genes for both early and late onset Alzheimer’s to
determine if these genes have an effect on the tendency to develop Alzheimer’s. I would do a
linkage study on the APOE gene, specifically the E4 allele to study whether
hypercholesterolemia has a marked impact on an individual developing Alzheimer’s due to a
build up of plaque, or whether this factor does not play a significant role.

Ethical considerations
• Older people diagnosed, they don’t have long to live – studies may decrease the quality
of life
• Due to the fact that they can’t remember very well, might forget they are part of a study,
may cause stress every time they have to be reminded
PARKINSONS
Phenotype
• 2nd most common neurodegenerative disease showing adult onset
• Due to a loss of dopaminergic neurons (dopamine helps control voluntary movement)
• Is a progressive movement disorder – gets worse over time
• Presents with a resting tremor, bradykinesia (can’t place hand or limb where they need
to go), rigidity and postural instability
• Influenced by genetic and environmental contributions
• Has an initial good response to dopamine-replacement therapy (L-dopa administered) –
replaces lost dopamine

How will I test this?

Genetic screening can be done early on for Parkinson’s candidate genes. This can be done by
sequencing the individual’s genome and looking for any potential markers.

Quantitative studies
Twin studies are quantitative studies done by using monozygotic and/or dizygotic twins as test
subjects. These studies aim to reveal the importance of environmental and genetic influences
on traits, phenotypes, and disorders. In this study the subjects were monozygotic and dizygotic
twins. Twin studies have demonstrated that Parkinson’s is a modestly heritable trait. Positively
identified mutations were found in multiple genes. These genes were found in families that
show autosomal recessive or autosomal dominant Parkinson’s disease. Multiple genes have
been identified in linkage analysis studies that could be susceptible for mutations that cause
Parkinson’s disease.
Advantages for twin studies are that environmental influences on a trait can be ruled out due to
the fact that usually both twins are raised in the same family environment. Disadvantages
include the fact that twins are not really representative of the general population they are
unique. Twins are also usually born prematurely with low birth rates; this may lead to an
abnormal expression of a phenotype later on in life.

Molecular studies
MAPT
• Located in a chromosomal interval that has a splice site that causes 2 haplotypes (H1 and
H2)
• H1 = Parkinson’s in Caucasian populations but not in Asian
Autosomal dominant
• SNCA
- codes for protein (α-synuclein) – a small pre-synaptic protein that modulated
neurotransmitter release and vesicular turnover (removes vesicles – recycles – new
vesicles formed)
- SNCA point mutations = rare, early onset PD + cognitive dysfunction
- overexpression = PD
- linked to aggregation of α-synuclein as well as neurotransmitter release and vesicle
turnover
• LRRK2 (PARK8)
- more than 40 mutations already reported that lead to an increased risk in developing
PD
- linked to a mishandling of α-synuclein
Autosomal Recessive
• 3 genes reported
• Resembles normal PD, but with much earlier onset
• Loss of function of these genes = decreased protection of dopaminergic neurons =
neuron death
• PARK 2
- most frequent
- screen for this during genetic screening
- linked to proteasomal and lysosomal degradation, as well as mitochondrial dysfunction
• PINK1 (PARK6)
- linked to proteasomal and lysosomal degradation, as well as mitochondrial dysfunction
• PARK7 (DJ1)
- very rare - <1%
- linked to oxidative stress and proteasomal degradation

How will I test this?

I would conduct a linkage study on the PINK1 gene to determine if its affects on proteasomal
and lysosomal degradation have a significant effect of the risk of developing Parkinson’s.

Ethical considerations
• Information Giving - diagnosis as closure (Test subjects felt relieve after they received all
of the information regarding their diagnosis), varying experience of how the diagnosis
was given (Test subjects also indicated that they have better experiences when receiving
bad news in private) and whether the level of information helped with coping (Subjects
indicated that receiving as much information as possible helped them to cope, while
others believed they were given too much information, preventing them from coping
with their diagnosis)
• Coping with PD - There were several factors that influenced coping: medication
management (principle of beneficence, since efforts were made to improve efficacy of
prescribed medication) support from health-care professional or family (subjects who
had constant support form loved ones, had better overall coping mechanisms), poor
access to health-care professionals (patients who could not access doctors, felt
discouraged), and impact of relationships within the team on the patient (when
healthcare professionals did not agree, conflict caused distress in the patient)
• Identity - Results from the study showed that physical changes as a result of Parkinson’s
had altered their identity and they experienced low self-esteem or had feeling of
worthlessness. They felt their identity had changed due to limitations of independence
(e.g. they could not drive) and compromises in relationships (they had to become
dependent on others ad felt like a burden
DEMENTIA WITH LEWY BODIES (DLB)
Phenotype
• Looks like Alzheimer’s, but localized to certain part of the brain (not global)
• 15% of all dementia cases
• Presents with progressive cognitive impairment with fluctuating course, recurrent visual
hallucination and Parkinsonism
• Overlap with AD and PD – presence of cortical and subcortical Lewy Bodies (fatty
deposits – plaques)
• Shows neurofibrillary tangles and amyloid plaques

Molecular studies
SNCA
• Also linked with autosomal dominant PD
• Copy number variants – number of triplications increase over time which leads to PD
with dementia (PDD) and presence of Lewy bodies
• Duplications – leads to PD
• Triplications – leads to PDD and DLB – starts with PD symptoms, progresses to look like
AD (cognitive decline)
LRRK2
• Also linked with autosomal dominant PD
PSEN1
• Seen in atypical AD with abundant Lewy bodies
APOE-ε4
• Leads to increased risk of developing DLB
• Responsible for Lewy body pathology in AD
Synuclein Families
• SNCA, SNCB, SNCG
• Seems to be most influential – responsible for vesicular recycling – if it doesn’t happen –
vesicles not getting removed after breakdown – accumulates – frms fatty Lewy body
deposits
• Studies need replication to confirm
FRONTOTEMPORAL DEMENTIA (FTD) AND FRONTOTEMPORAL LOBAR
DEGENERATION (FTLD)
Phenotype
• Heterogenous group of syndromes
• Present with gradual and progressive change in behaviour and personal conduct and/or
by a progressive language dysfunction (frontal lobe=higher intellectual abilities,
personality etc.)
• Initial symptoms restricted to frontal lobe
• Rarely present before 75
• Shows similarities to PD or ALS
• We don’t know too much due to the fact that it only occurs later in life and the decline is
very rapid, we therefore cant see how it progresses throughout an individuals life

Molecular studies
Tau Positive
• Linked with PD
• MAPT gene
- Codes for Tau protein which are microtubules that support axons
- Faulty gene = degeneration of proteins = fatty deposits form on axons
- more than 40 mutations found
- different isoforms due to splicing
• 4 repeat Tau haplotypes
• Related to late onset of PD and FTD
Tau Negative
• Also called DOD1 – linked to negative ALS
• More prone to interaction with other genes
• FTLD-TDP (GRN gene)
- codes for growth factor
- more than 70 mutations identified
- leads to loss of function
- Autosomal Dominant inheritance
• TDP-43 (TARDBP)
- highly conserved and widely expressed
- codes for a DNA/RNA-binding protein that has regulatory cellular functions
(transcription and splicing)
• VCP
- co-morbid with ALS
ALS (MOTOR NEURON DISEASE)
Phenotype
• Presents with rapidly progressive degeneration of motor neurons in brain and spinal
cord
• Individual first loses voluntary movements, eventually they lose involuntary movements
(breathing) = death
• Leads to paralysis and death within 1-5 years
• Low prevalence – 5/100000
• There’s nothing wrong with the cognitive function of an affected individual, they just
can’t move the way they want to move
• Loss of motor neurons
• Presence of ubiquitin-positive fatty deposits in remaining motor neurons
• Presence of pathological TDP-43 aggregate deposits – ALS and FTD are on same
clinicopathological spectrum
• In 10% of cases theres also a cognitive decline and dementia (overlap with FTLD)
• Familial = 5-10% of cases
• Sporadic = rest

How will I test it?

Genetic screening can be done early on for ALS candidate genes. This can be done by
sequencing the individual’s genome and looking for any potential markers.

Quantitative studies
Family studies are ideal for studying Familial ALS as it shows a autosomal dominant inheritance
pattern, it is therefore easy to track the possible candidate genes through generations in a
family that show a risk in developing ALS. It is however more difficult to do quantitative studies
on sporadic ALS as it shows no clear inheritance pattern. However, a family study can still be
used to look for any correlations between environmental factors and the risk of developing
sporadic ALS. Disadvantages of family studies include the fact that it is difficult to find large
enough families to study, as well as fact that candidate genes may be unique to specific families
within a population as a result of possible inbreeding, this may make studies difficult to replicate

Molecular studies
Familial
• Autosomal dominant inheritance
• 10 different loci (ALS 1-10) – cause pure ALS phenotype by genetic linkage – have
different levels of penetrance
• 7 of the loci have disease causing mutations – these mutations change the proteins they
encode to such an extent that they are either completely different or completely absent
• SOD1
- 10-15% of cases
- more than 100 mutations
- autosomal dominant inheritance
- high prevalence in Scandanavian countries (geographically isolated)
- linked to toxic aggregation of SOD1, oxidative damage, mitochondrial dysfuntion, RNA
destabilization, impairment of axonal transport and glutamate excitotoxicity
 • TARDBP
- autosomal dominant inheritance
- encode for a binding protein
- linked with ALS and FTD
- more than 30 mutations
- linked to RNA processing and formation of inclusion bodies
• All genes linked with ALS are involved in DNA/RNA processing or vesicular recycling
• Other genes:
- ALS 2 (linked with endosome/membrane trafficking)
- ANG (affects rRNA transcription)
- FUS (linked with RNA processing and formation of inclusion bodies)
- SETX (linked with DNA/RNA processing)
- VAPB (linked with vesicle trafficking)
Sporadic
• Most ALS cases don’t show clear familial segregation – randomly occurs
• Genetically complex form of the disease
• Not clear how genes interact/contribute
• Difficult to replicate studies (genetic expression in brain only available post-mortem –
the process of dying changes gene expression – results may be different)
• Gene desert
- areas we don’t know what they code for
- also linked with FTD cases
• UNC13A
- candidate gene
- linked with synaptic vesicle priming

How will I test it?

I would do a linkage mapping study on the UNC13A gene to study whether there is a significant
link between its role in synaptic vesicle priming and a mutation that may cause ALS.

Ethical considerations
• Consent
• Don’t have long to live – may want to spend time with family
• Lose the ability to communicate, may not be able to give and verbal information
MOOD
Phenotype
• Most common disorder
- major depressive disorder (MDD) – 16,6%
- dysthymia – less severe, more chromic
- bipolar (major highs and lows) – 3,9%
• Relates to how one is feeling (happy, sad, depressed etc)
• Women are at a higher risk of developing these disorders
• Disorders are episodic and recurrent in most cases
• The likelihood of reoccurrence increases with each depressive episode – “what doesn’t
kill you makes you stronger” is a lie – every episode makes you more vulnerable –
become more recurrent until you can’t get back to a non-depressive state
• Each recurrent episode makes long term alterations in the neurobiological function of
the individual
• High variability (that’s why there are so many meds) – sensitive to state dependent
factors (certain amount of variability to these factors – is a person susceptible to all kinds
of stress? Or just specific kinds?)

How would I test it?

A clinical questionnaire could be administered where by the patient rates their moods in certain
situations. Also a scan of the patients brain could be done to determine how reactive the
Serotonergic, Dopaminergic as well as the NE pathways are during certain situations, or just
generally.

Quantitative studies
Family studies are ideal to study mood disorders as it allowed one to track alleles associated
with the disorders through generations and make a deduction about whether environmental
factors play a role as well. Family studies done continuously showed that mood disorders are
concentrated within a family. In multiple studies, the first-degree relatives of probands with
anxiety disorder showed a high risk of developing the disorder as well. However, environmental
triggers such as a traumatic childhood event or an unsafe family environment may also
contribute to the risk of developing a mood disorder. A disadvantage of family studies is that it
is difficult to find large enough families to study these days. Also, the fact that candidate genes
may be unique to specific families within a population as a result of possible inbreeding, this
may make studies difficult to replicate.

Molecular studies
Serotonergic System
• Increased activity of autoreceptor (HRT1B) – shuts down system
• Too many transporters (SERT) – premature reuptake
• TPH-depletion
- not enough 5-hydroxytryptophan
• Treated with SSRI’s – block transporters
• 5HTTLPR
- linkage studies
- susceptibility variant
• Leads to suicidal behaviour, impulsivity, aggression, eating disorders, OCD, anxiety
disorders, personality disorders, SAD, alcohol use disorders
Noradrenergic System
• Less clear
• Increased sympathetic NS stimulation = lover CNS NE activity
Dopaminergic System
• Main culprit
• Low levels of CSF HVA – shows decreased production of dopamine – not sufficient for
maintenance
• Increased levels of plasma HVA – due to overactive enzymes – dopamine broken down –
none stored in vesicles
• Low β-hyroxylase activity due to dysfunction in gene – L-Dopa not converted to
dopamine
• Too many transporters
• Overactive autoreceptor (DRD1)

How would I test it?

I would do a study on the dopaminergic system, specifically a linkage study to determine what
variant of the gene that codes for transporters least to too many transporters being present on
the presynaptic neuron, and how great an effect this has on the development of mood
disorders.

Ethical considerations
• Clearance from the relevant Ethical committee in charge in the region of research.
Ethical clearance was also required from the local Department of Public Health. Certain
regions have ethical parameters and rights which may not be infringed upon during an
experiment of any kind.
• To ensure that the subject’s well-being was ensured during the experiment, an
independent psychiatric evaluation should be done on each of the patients before the
experiment begins
• It is important that when data are being collected for a study or experiment the subjects
know exactly what the study/ experiment entails, so that a subject may make an
educated decision on whether to participate or not
• All information or data collected should be given to the subjects
ANXIETY
Phenotype
• How an individual perceives stress
• Can be a precursor to mood disorders – prolonged periods of anxiety lead to a
depressive state
• Development of mild forms of anxiety and severe responses in a stressful situation =
adaptive evolutionary step against environmental/external or self-triggered/internal
threats
• Anxiety disorders are maladaptive conditions where individuals show disproportionate
responses to stress (see stress and exaggerate it)
• Most frequent psychiatric illness
- generalized stress disorder – 6%
- social phobia – 12%
- panic disorder – 5%
- PTSD – 6,8%

How would I test it?

A clinical questionnaire could be administered where by the patient rates how anxious they feel
in certain situations. Also a scan of the patients brain could be done to determine how reactive
the Serotonergic as well as the NE pathways are during certain situations that may cause
anxiety.

Quantitative studies
Family studies are ideal as they may help determine the genetic vs environmental factors of a
specific phenotype. Alleles can also be tracked through generations. Family studies done
continuously showed that anxiety disorders are concentrated within a family. In multiple
studies, the first-degree relatives of probands with anxiety disorder showed a high risk of
developing the disorder as well. It was also found that females relatives showed a much higher
prevalence to the morbidity of anxiety disorder than their male counterparts. A disadvantage of
family studies is that it is difficult to find large enough families to study these days. Also, the fact
that candidate genes may be unique to specific families within a population as a result of
possible inbreeding, this may make studies difficult to replicate.

Molecular studies
Noradrenergic System
• Increased NE activity = increased anxiety
• Vasoconstriction of peripheries + increased HR = anxiety and panic
• α2 receptors (autoreceptors) – increased stimulation =decreased anxiety due to
shutdown of system
Serotonergic System
• Decreased tryptophan due to low protein diet = decreased serotonin production
• Too many transporters (SERT)
• Overactive enzymes (MAO-A/B) – breakdown serotonin (treated with MAOIs)
• Decreased activity in hetroreceptors (HTR2A)

How will I test it?

I would do further testing on the serotonergic pathway to determine whether a marked
increase in the intake of Tryptophan in the diet of an individual suffering from anxiety would
have any effect on the expression of the disorder.

Ethical considerations
• Clearance from the relevant Ethical committee in charge in the region of research.
Ethical clearance was also required from the local Department of Public Health. Certain
regions have ethical parameters and rights which may not be infringed upon during an
experiment of any kind.
• To ensure that the subject’s well-being was ensured during the experiment, an
independent psychiatric evaluation should bedone on each of the patients before the
experiment begins
• It is important that when data are being collected for a study or experiment the subjects
know exactly what the study/ experiment entails, so that a subject may make an
educated decision on whether to participate or not
• All information or data collected should be given to the subjects, in order to minimize
their anxiousness
SCHITZOPHRENIA
Phenotype
• Affects 1% of population
• Presents in late adolescence to early adulthood (18-24)
• Presents earlier in males
• Lifelong disorder – reduces life expectancy by around 10 years – suicide
• Shows discontinuous variation – once you have it, you have it
• Isolated to the brain
• Shows high degree of heritability
• Traumatic life experiences during developmental years can be a triggering event if the
individual is already has the genetic predisposition
• Positive symptoms
- something gets added
- most dramatic – psychosis
- hallucinations - sensory experiences in the absence of stimuli – eg, voices in head
- delusions – fixed, false belief – can’t be convinced otherwise – it is that persons reality
(can be mundane or bizzare)
- cognitive processes are disorganized, form loose associations and have illogical
reasoning
- most responsive to antipsychotic meds
• Negative symptoms
- something gets subtracted (loss/deficit)
- can be accompanied with + symptoms
- presents with decreased emotional reactivity, paucity of speech, loss of motivation,
inability to experience pleasure
- extreme depression – constant depressive state – people often hurt themselves to try
feel something
- difficult to treat, but responds well to meds
• Cognitive impairment
- presents with modest reduction in IQ, distuptive attention, decreased problem-solving
abilities, decrease in verbal declarative memory, decreased verbal fluency and delayed
word recall
- difficult to treat, but responds well to meds
- looks like AD, but no brain shrinkage
Endophenotype
• Only applicable to first-degree relatives
• Core symptomatic features
- subtle abnormalities in cognitive function and attention
- social oddness
- motor clumsiness
• Used to indicate if a child is at high risk

How would I test it?

Genetic screening can be done early on for Schizophrenic candidate genes. This can be done by
sequencing the individuals genotype and looking for any potential markers.

Quantitative studies
Twin studies
 • Concordance for MZ twins = 60% (high genetic influence)
• DZ twins = 10% only
• Disconcordance in MZ twins due to epigenetics – environmental influences can switch
genes on and off
Adoption studies
• Risk for Schitzo is unchanged, regardless of family environment

How would I test it?

I would implement a twin study as it is one of the 2 best ways to try and determine whether the
acquired trait is inherited or acquired due to the environment. The similar the phenotypes of
the subjects, e.g. sex and eye colour, the better indication of monozygotic twins, which are
more similar than dizygotic twins, and therefore are the more closely related pair of twins. The
degree of relatives is quite important when trying to determine the heritability of a particular
phenotype as it is in conjunction with the amount of similar genes between the participants.
If both of the twins develop schizophrenia, then we can assume the disease is inherited, due to
the genetic similarities, and if one of the twins develop the disease then we assume that it is
environmental. Previous twin studies have been done before about Schizophrenia and it has
been seen that the heritability of schizophrenia is around about 80% and it is not only a result of
genetic influences but is also in reference with gene-environment interactions that moderate
the expression of the genes which result in the diseased phenotype. Advantages for twin studies
is that environmental influences on a trait can be ruled out due to the fact that usually both
twins are raised in the same family environment. Disadvantages include the fact that twins are
not really representative of the general population, they are unique. Twins are also usually born
prematurely with low birth rates, this may lead to an abnormal expression of a phenotype later
on in life.

Molecular studies
Association studies
• Found genes involved in brain development and neurotransmitter
GWAS
• Found regions of interest on chr 1,2,15,22
• Copy number variants (triplet repeats) – number of copied of DNA region differs in
probands vs controls – if the number of repeats exceed a certain threshold there is an
increased risk
Dopamine hypothesis
• Don’t know if it’s a defective system that causes schitzo, but we do know that
stimulating the system helps treat the symptoms
• More than one system involved
• Need to investigate post-transcriptonal modifications (DRD2 splice site) – there are
interrelationships between proteins and families of proteins (need to look at
RNA/protein to know how DNA is being expressed)
• Post-mortem findings were inconclusive (dying changes transcriptional profile)
• DRD2
- has a high affinity for antipsychotics – stimulated specifically in individuals with
hallucinations
- inconsistent evidence of alterations (due to splice site, can be hetro- or autoreceptor)
 • DRD3
- expression regulated by BNDF – helps brain grow – epistatic interactions – need specific
variants for specific phenotypes
• DRD4
- disproportionatly high affinity for antipsychotics
- shows inconsistent alterations – different phenotypes
• COMT
- enzyme becomes temp dependent
- VAL = high functioning form of enzyme – seems to be more prevelant in individuals
with schitzo – dopamine gets briken down too quickly
- shows inconsistent results

How would I test it?

I would use linkage mapping to try and determine the similarities between the twins. Using this
method of comparing closely related individuals is the best way to try and identify the genes
involved in the disease within a family. There have been around about 30 gene loci that have
been associated with schizophrenia through GWAS which generally focuses on single-nucleotide
polymorphisms to determine the copy number variants, CNV, which are considered to be
numerous genes that the individual has which is different from an effected person with
schizophrenia, that are located usually on the 1,2,15 and 22 chromosomes for this disease. I
would do further studies on the link between the dopamine pathway and Schitzophrenia as
there is have been the least studies on it and understanding this link may be the key to better
management and treatment of the disorder.

Ethical considerations
• When dealing with Schizophrenia patients you are usually dealing with people who are
mentally struggling so they may not be physically or emotionally up to the tests that you
have provided for them as simple as they may be.
• You may only cause them more harm emotionally as you conduct your tests as you may
be conflicting their opposing world view.
• Schizophrenics may think that you are trying to hurt them even if you are going to do a
harmless procedure.
• Getting consent from individuals who are diagnosed with schizophrenia to do the study
is also quite difficult as one day they may emotionally feel fine and the next day they
may feel differently.
• Most of the older patients also suffer from long term memory loss and so they would
most probably want to spend as much time as possible with their family before they
forget them as well as younger patients would probably want spend time with their
family before the psychosis gets worse and they can’t relate to their family anymore.