Behavioral Science - Genetics in Psychiatry - Thomas L. Schwartz

Question 1

T/F – Genetics of most hereditary disorders (70 % inheritance) can be mapped to specific genes

Answer 1

False.
require hundreds of mutated genes to produce spectrum of clinical symptoms that would cause someone to meet diagnostic criteria for specific disorder

Question 2

High or low genetic heritability? 
ADHD? 
Depression? 
Anxiety? 
Schizophenia?

Answer 2

ADHD? - HIGH
Depression - LOW
Anxiety - LOW
Schizophenia - HIGH

Question 3

Epistasis describes ___

Answer 3

the effect of one gene being dependent on the presence of one or more ‘modifier genes’

Question 4

What are epigenetics? Does it involve changes in DNA?

Answer 4

describes change in gene expression due to environmental influences, NOT change DNA

Question 5

Nigrostriatal dopamine pathway:
Originates ___ projects to ____
Controls ___

Answer 5

Originates at substantia nigra
Projects to striatum/basal ganglia
Controls motor function and movement

Question 6

Mesolimbic dopamine pathway:
Originates ___ projects to ____
Controls ___

Answer 6

Originates at VTA of midbrain
Projects to nucleus accumbens
Controls reward and perception of pleasurable sensations, delusions and hallucinations of psychosis

Question 7

Mesocortical dopamine pathway:
Originates ___ projects to ____
Controls ___

Answer 7

Originates at VTA of midbrain
Projects to DLPFC or VMPFC
Controls executive functions
VTA > DLPFC Controls cognitive symptoms of schizo
VTA > VMPFC controls affective symptoms of schizo

Question 8

Tuberoinfundibular dopamine pathway:
Originates ___ projects to ____
Controls ___

Answer 8

Originates at hypothalamus
Projects to anterior pituitary
Controls prolactin secretion

Question 9

Tuberoinfandibular DA pathway
hypofunction?
hyperfunction?

Answer 9

hypofunction? hyperprolactinemia

hyperfunction? hypoprolactinemia

Question 10

Mesolimbic dopamine pathway:
hypofunction?
hyperfunction?

Answer 10

hypofunction? amotivation, apathy

hyperfunction? addiction, hallucinations

Question 11

Nigrostriatal dopamine pathway:
hypofunction?
hyperfunction?

Answer 11

hypofunction? dyskinetic movement, parkinsonism

hyperfunction? dyskinetic movement

Question 12

Mesocortical dopamine pathway:
hypofunction?
hyperfunction?

Answer 12

hypofunction? inattention

hyperfunction? hypervigilance, insomnia

Question 13

Which dopamine pathways are involved in schizophrenia? Which are hypoactive which are hyperactive?

Answer 13

Mesolimbic - hyperactive

Mesocortical - hypoactive

Question 14

What could a mutation in COMT cause?

Answer 14

Schizophrenia ** if paired with other mutations

COMT is catachol-O-methyl transferase > degrades DA mutation usually generates high levels of DA

Question 15

What are 4 genes involved in dopamine pathways that could lead to schizophrenia symptoms if many mutations occur?

Answer 15

COMT
Tyrosine hydroxylase
D2R (dopamine receptor 2 - sometimes called DAR2)
D3R

Question 16

What does DISC1 do?
Mutation of DISC1 is associated with what disease?
What is the MAO

Answer 16

DISC1 normally facilitates neurogenesis, cell migration, differentiation, synaptogenesiss and selective pruning of synapses

schizophrenia

epistatic mutation - multiple other downstream genes are affected

Question 17

What are 2 genes that DISC1 mutation can affect?

Answer 17

ErbB4, NRG

Question 18

Mutation of DISC1 is associated with what disease?

What is the MAO

Answer 18

schizophrenia

epistatic mutation - multiple other downstream genes are affected

Question 19

T/F it is possible to have normal dopamine levels and still have schizophrenia

Answer 19

True

Can be due to disrupted neurodevelopment that doesn’t affect dopamine

Question 20

characteristic brain activity patterns on fMRI associated with gene activation/deactivation/mutation

Answer 20

endophenotype

Question 21

What is one plausible explanations for mesocortical hypoactivity and mesolimbic hyperactivity?

Answer 21

dysfunctional PFC results in loss of top down control of limbic DA release

Question 22

Hyperactive mesolimbic system is associated with mutations in which genes?

Answer 22

D2R, Tyrosine hydroxylase, MAOs

Question 23

Hypoactive mesocortical system is associated with mutations in which genes?

Answer 23

COMT and D3R

Question 24

What are 2 genes involved in ADHD

Answer 24

D4R, D5R

Question 25

If enough ADHD associated mutations occur what could occur?

Answer 25

schizophrenia symptoms

Question 26

5 gene mutations involved in ADHD?

Answer 26

``` DRD1 (DRD = DAR = D1R) DRD2 DRD4 DAT1 DISC1 (also schizo) ```

Question 27

In ADHD what brain regions are affected? Hyper vs Hypo active?

Answer 27

Anterior cingulate cortex and mesocortical pathway is hypoactive other cortical regions (e.g. insula) not associated with vigilance and concentration are hyperactive - (inefficient compensation)

Question 28

what two genes are implicated in mesocortical and anterior cingulate hypofunction in ADHD?

Answer 28

DRD4 DRD5

Question 29

In Depression which pathways/brain regions are involved

Answer 29

mesocortical system is primarily involved DLPFC is hypoactive VMPFC between right and left hemispheres (emotional processing areas) are hyperactive limbic regions are also hyperactive

Question 30

What genes are involved in major depressive disorder?

Answer 30

DAT, DRD4, COMT could result in schizo if too many mutations develop

Question 31

In major depressive disorder - hypoactivity in DLPFC is linked to _____ Hyperactivity in VMPCF and limbic areas are linked to ____

Answer 31

Poor DA tone Serotonin mutations

Question 32

Inheritance of which 3 genes might contribute to hypoactivity of the DLPFC / disfunction of the mesocortical pathway in major depressive disorder?

Answer 32

COMT, DAR4, DAT dysfunctional VTA is responsible for hypoactivity of DLPFC (ventral tegmental area of the midbrain --> origin of mesocortical DA pathway)

Question 33

What is the precursor to serotonin?

Answer 33

tryptophan

Question 34

True or false, the 5HT pump can also pump in tryptophan

Answer 34

False - serotonin and tryptophan pumps are distinct

Question 35

Put these in sequence: TRY-OH, serotonin, VMAT2, AAADC, tryptophan, 5HTP What pathway is this?

Answer 35

Tryptophan>TRY-OH>5HTP>AAADC>5HT (serotonin)>VMAT2 Serotonin synthesis: Tryptophan is pumped into cell via tryptophan specific transporter then converted to 5HTP by tryptophan hydroxylase (TRY-OH; aka TPH), which is then converted to serotonin/5HT by AAADC and packaged in vesicles by vesicle monoamine transferase 2 (VMAT2)

Question 36

T/F serotonin can be brought back into the serotenergic axon terminal via SERT

Answer 36

true SERT = serotonin reuptake transporter

Question 37

T/F low levels of intracellular serotonin/5HT can be broken down by MAO-A

Answer 37

False - HIGH (not low) levels of intracellular serotonin can be broken down by MAO-B (not A)

Question 38

T/F extracellular serotonin can be broken down by COMT

Answer 38

False - this beaks down DA

Question 39

Extracellular serotonin can be broken down by ___?

Answer 39

MAO A and/or MAO B

Question 40

T/F serotonergic projections originate in the locus cereleous?

Answer 40

False - Serotonin projections originate in the Raphe Nucleus

Question 41

T/F serotonin projections are both ascending (into the brain) and descending (down the spinal cord)?

Answer 41

True - NE projections from LC do the same

Question 42

What do the descending serotonin pathways do?

Answer 42

regulate pain (descending inhibitory system)

Question 43

``` Hyperfunctioning lymbic serotonin pathways cause these symptoms: 1 2 3 4 ```

Answer 43

Panic Worry Obsession Depression

Question 44

T/F hyperfunctioning lymbic pathways have high levels of SE

Answer 44

False - may have poor serotonin acitvity

Question 45

What are 3 commonly mutated genes involved in the serotonin Genetics of MDD/Anxiety/Eating Disorder/BPDO?

Answer 45

5-HT2A 102 T/C 5-HTTLPR promoter TPH (tryptophan hydroxylase)

Question 46

5-HTTLPR promoter regulates the expression of the 5-HTTLPR gene. What does the 5-HTTLPR gene code for?

Answer 46

SERT

Question 47

In depression/anxiety the cingulate cortex and amygdala are hypoactive of hyperactive? What NT is throught to be responsible

Answer 47

Hyperactive Poor serotonin tone

Question 48

in anxiety and depression the mesolimbic system is hyper of hypoactive?

Answer 48

hyperactive - also the medial frontal cortex

Question 49

Which serotenergic gene mutations cause hyperactivity of the mesolimbic system and medial frontal cortex in anxiety/depression?

Answer 49

5HT2R, 5HTTLRP, TPH Serotonin 2 receptor, CERT, tyrosine hydroxylase

Question 50

5HT2R, 5HTTLRP, TPH mutations in axiety and depression result in increased or decreased firing and reactivity of the Raphe nucleus?

Answer 50

Increased reactivity and firing - don't really understand this.. less serortonin reaches the

Question 51

Put these in order: NE, Tyrosine, VMAT2, DOPA, DDC, TOH, DBH, DA

Answer 51

Tyrosine> (TOH) tyrosine hydroxylase>DOPA>(DDC) dopamine decarboxylase>DA>(DBH) dopamine beta hydroxylase>NE>VMAT2

Question 52

Hyperfunctioning lymbic NE pathways cause these symptoms: 1 2 3

Answer 52

Panic worry arousal NE might be too high! (opposite of serotonin)

Question 53

Hypofunctioning corticofrontal NE pathways cause these symptoms: 1 2

Answer 53

ADHD | Depression

Question 54

What does hypofunctioning of DA NE pathways cause

Answer 54

loss of possitive emotion/affect

Question 55

depressed mood; loss of happiness, interest, or pleasure; loss of energy or enthusiasm; decreased alertness; and decreased self-confidence are associated with hypofunctioning of which NT systems? Increase in negative affect or loss of positive affect?

Answer 55

DA + NE hypofunction Loss of positive affect

Question 56

depressed mood, guilt, disgust, fear, anxiety, hostility, irritability, and loneliness associated with hypofunctioning of which NT systems? Increase in negative affect or loss of positive affect?

Answer 56

SE (sometimes NE) Increase in negative affect

Question 57

What symptoms are associated with an decrease in positive affect?

Answer 57

depressed mood; loss of happiness, interest, or pleasure; loss of energy or enthusiasm; decreased alertness; and decreased self-confidence

Question 58

What symptoms are associated with an increase in positive affect?

Answer 58

depressed mood, guilt, disgust, fear, anxiety, hostility, irritability, and loneliness

Question 59

Do PTSD patients have increased or decreased negative or positive affect?

Answer 59

Increased negative affect

Question 60

What is the difference between Met vs Val alleles of COMT?

Answer 60

Met-COMT = low function/monoamine degradation so high NE/DA = increased NE/DA and anxiety in limbic areas VAL--COMT = high function = low NE/DA in cortex (in depression VAL allele of COMT could explain low concentration of NE and symptoms of low energy.poor concentration)

Question 61

X inactivation of MAO results in what?

Answer 61

two copies of MAO expressed - Faster degradation of monoamines and lower levels available to cortex = depression in females

Question 62

ADHD is associated with what mutation? How does this affect neurotransmitter levels? What brain regions are affected? Hypo or hyper active?

Answer 62

COMT Val allele results in increased monoamine breakdown (so less NT) depriving the frontal cortex and cigulate cortex making them hypoactive