Lecture 5: Genetics

Question 1

_________ is individual genetic make-up whilst ______ are physical and behavioural characteristics

Answer 1

Genotype – individual genetic make-up

Phenotype – physical and behavioural characteristics

Question 2

Genetic epidemiology looks at whether there is evidence for _______________

Answer 2

heritability of a disorder

- If so, it looks at whether it appears to be a single gene or multiple genes?

Question 3

What is the difference between Molecular genetics and molecular biology ?

Answer 3

Molecular genetics looks at whether the disorder is associated with specific genes and whether the disorder can be liked to gene variations.

Molecular biology, on the hand, looks at a candidate gene and what it does.

Question 4

What have we learned from Family studies?

Answer 4

• Risk is never as large as the genetic relatedness
• First degree relatives have a greater risk than the population
• MZ twins and children of two parents with SZ have the highest risk (about %50)
• Siblings have lower risk than DZ twins
• Parents have lower risk than children or siblings

Question 5

Therefore, Risk not as great as _____________

Answer 5

genetic relatedness

Question 6

What is meant by MZ twins not 100% concordant?

Answer 6

Genes are not enough, there’s environmental (pre- and post-natal factors)

Question 7

DZ twins at higher risk than __________

Answer 7

siblings

Question 8

What does DZ twins at higher risk than siblings mean?

Answer 8

Shared pre-natal environment is important

But not enough

Question 9

Parents at lower risk than __________

Answer 9

children

Question 10

Why would Parents be at lower risk than children?

Answer 10

Parents environment may have been different
ie, may not have had a parent with SZ
More stable family, higher SES, etc

Question 11

How do we examine the relative contributions of genetic vs environmental factors?

Answer 11

Through adoption studies

Question 12

What did the adoption studies of children with SZ mothers reveal?

Answer 12

Children of SZ mothers more likely to develop SZ

Twins reared apart have similar risk

Question 13

But, children of SZ mothers adopted into __________ also show higher risk of developing SZ or SZ-spectrum disorders

Answer 13

low-functioning families

Question 14

SZ is genetically _______, but not genetically ________

Answer 14

SZ is genetically mediated, but not genetically determined

Question 15

A Meta-analysis showed that _____ of risk genetically determined; _____ environmentally determined

Answer 15

Meta-analysis: 81% of risk genetically determined; 11% environmentally determined

Question 16

Relatives of people with SZ are also______ more likely to have schizotypal or paranoid personality disorder

Answer 16

4-5 times

Question 17

Relatives of people with SZ also have a higher risk of ________

Answer 17

other SZ-spectrum disorders

Question 18

Relatives of people with SZ do not have greater risk for _________

Answer 18

affective disorder, anxiety disorders or alcoholism

Question 19

There may be a link between SZ and which other disorder?

Answer 19

Bipolar disorder

Question 20

Which is Consistent with _______ conferring risk for psychotic disorders

Answer 20

multiple genes

Question 21

In the study of transmission of genetic risk, transmission models predict ____________________

Answer 21

what we should see and then match it to the evidence

Question 22

In the case of SZ, what type of model does not fit?

Answer 22

A model of simple transmission of a single gene (or locus) does not fit

Question 23

In the multiple gene models of SZ, multiple genes contribute to a __________, _______, ________ to develop SZ

Answer 23

liability, susceptibility or predisposition

Question 24

If there are multiple genes and inheritance is not simple, then genes are likely to be common _____________________

Answer 24

in the general population

Question 25

The _______ model predicts that many genes contribute to risk, but no one gene or genes is necessary

Answer 25

polygenetic

Question 26

The _____________ model proposes that risk is a continuum including genetic and environmental factors

Answer 26

multifactorial threshold

Question 27

In the multifactorial threshold model, the presence of _____________________ adds to risk

Answer 27

each gene or environmental factor

Question 28

Which model proposes that genetic risk factors interact?

Answer 28

The gene interaction model

Question 29

The gene interaction model proposes that genetic risk factors interact. This is more consistent with _____________

Answer 29

fall-off rate of risk in relatives

Question 30

Both ________ and ____________ likely contribute

Answer 30

Both additive risk and gene interactions likely contribute

Question 31

Environmental factors are also critical. Give an example.

Answer 31

Prenatal stressors: maternal stress and starvation

Question 32

What did the Studies of the rate of SZ following famine in Netherlands show?

Answer 32

- twice likely to develop SZ (environmental risk factor was famine) ***Children estimated to have been conceived during 1944-45 were twice as likely to develop SZ (But, only 25 cases!)

Question 33

What were the findings of the Anhui province study [ Rate of SZ following famine in China (1959-61)]?

Answer 33

- Twice likely to develop SZ (environmental factor was famine) Children born in 1960 and 1961 were twice as likely to develop SZ (large number of cases)

Question 34

What is the difference between linkage and association?

Answer 34

Linkage examines the whole genome looking for a relationship between a location and the disorder Association tries to identify the relationship between one gene and the disorder Moreover, Association Identifies a “candidate” gene based on relationship to one aspect of the phenotype (e.g, A gene involved in dopamine regulation, brain region)

Question 35

What are the difficulties in conducting linkage?

Answer 35

- Need multiple generations of the same family | - Hard to replicate

Question 36

Which one is the most powerful technique, linkage or association?

Answer 36

Association - More specific, powerful technique

Question 37

Linkage takes advantage of ___________________

Answer 37

naturally occurring gene recombination

Question 38

Genes that recombine frequently are ____________

Answer 38

further apart

Question 39

Genes that recombine frequently are further apart. Which means what?

Answer 39

- Either on the same or different chromosomes | - Greater distance creates more chances for recombination

Question 40

Genes that recombine ________ are closer together or “linked”

Answer 40

less frequently

Question 41

With the recombination frequency of many genes, we can estimate ____________________________

Answer 41

how far apart they are and their relative locations

Question 42

Fewer generations make linkage studies _________

Answer 42

more difficult.

Question 43

What is another limitation of linkage studies?

Answer 43

You need large numbers of well-characterized families, which is not easy.

Question 44

The results of linkage studies to date are ________ and ________

Answer 44

not very conclusive and hard to replicate

Question 45

What happens once a location is identified? candidate genes known to be close to that location can be studied using _________________

Answer 45

association studies.

Question 46

There is evidence for linkage to ____________ and _________

Answer 46

several chromosomes and locations

Question 47

In regard to association, what does it mean to test whether affected people are more likely to have a certain gene or gene variant?

Answer 47

To find a candidate gene

Question 48

When associations look at individuals as opposed to families. Which specific question are they trying to answer?

Answer 48

Is a specific candidate gene more common in those with SZ compared to those without?

Question 49

Most candidate genes related to the ____________ systems

Answer 49

dopamine, serotonin and GABA

Question 50

Associations are limited by ____________

Answer 50

what we know about the pathophysiology of SZ

Question 51

What does GWAS stand for?

Answer 51

Genome-wide association studies

Question 52

GWAS Compare SZ and controls across the ________

Answer 52

entire genome

Question 53

In GWAS studies, how many gene locations can be assed at the same time? And what are they testing for?

Answer 53

Millions of gene locations can be assessed at the same time | Tests the inheritance of allele (gene) variants

Question 54

To control multiple comparisons, you need ______

Answer 54

very large samples

Question 55

What were the main findings of the Multi-center study (2009)? How many potential location did they find? On which chromosomes? How many genes may contribute to the risk? Similar genes also contribute to which disorders?

Answer 55

- Found four potential locations (2 on chromosome 6) - Also found that thousands of genes may contribute to risk - Further, similar genes also contribute to risk for bipolar disorder and schizotypal personality disorder

Question 56

The Multi-sample GWAS Schizophrenia Working Group (2014) found _______ significant gene locations

Answer 56

108

Question 57

The Multi-sample GWAS Schizophrenia Working Group (2014) also found that these genes were expressed in which parts of the brain?

Answer 57

- Frontal (working memory, planning, attention) - Angular gyrus (language) - Inferior temporal (complex visual, faces, memory)

Question 58

What was the key receptor in relation to SZ?

Answer 58

Dopamine D2 receptor

Question 59

What were the key immune response associated with SZ?

Answer 59

CD 19 and 20

Question 60

Name the three organs where these genes were less expressed (less relevant)

Answer 60

-Kidney, liver, muscles

Question 61

What can we conclude from GWAS studies

Answer 61

That there are many genes expressed in various locations but we don't know if these are a cause or a consequence of SZ.

Question 62

However, what is one finding that is relevant from GWAS studies?

Answer 62

Greater risk with greater number of risk genes present

Question 63

Discussed the overview of results in GWAS studies. - The results of GWAS studies have _______________ - Each gene contributes _________________ - Supports the idea that _________________

Answer 63

- not always reproduced the results of candidate gene studies - only a small effect - a large number of common genes with small effects contribute to the disorder

Question 64

What is meant by "a large number of common genes with small effects contribute to the disorder"? - Each common gene might account for_____ of the risk - Together, they would only account for ____ of the total risk

Answer 64

- Each common gene might account for 1-2% of the risk | - Together, they would only account for 25-50% of the total risk

Question 65

What is the Common disease, rare variants hypothesis? (hint: what is the difference between common and rare genes in terms of effect?)

Answer 65

- Many common gene variants of small effect - Rare gene variants of large effect (which can cause SZ)

Question 66

Further, 2009 study found that similar genes are associated with both SZ and _____ supports the idea of ______

Answer 66

- Bipolar | - common gene spectrum

Question 67

What is a limitation of family studies?

Answer 67

Family studies assume that environment is constant and that genes and environment do not interact (we know that this is not the case)

Question 68

What are other limitations of these types of studies we covered in this lecture? - SZ symptoms are _____________ - No ________ at the individual level - Genetic studies are only as good as________ - SZ and other disorders part of _____________ - Overlap in risk with other disorders means ______

Answer 68

- variable and sub-types (e.g., positive/negative symptoms) not clear - diagnostic bio-marker - as our diagnostic criteria - a spectrum with shared risk. - results are not specific

Question 69

We can conclude that SZ is genetically _______, but not genetically _______

Answer 69

SZ is genetically influenced, but not genetically determined

Question 70

___________ genes are involved. The specific genes likely vary between ________ and _____________

Answer 70

- Multiple - individuals - families

Question 71

Part of the genetic risk is accounted for by ______ variants that are _____ risk individually

Answer 71

- common | - low

Question 72

There also an accounted for ________

Answer 72

rare, high-risk variants

Question 73

Risk is likely ______________________

Answer 73

Risk is likely additive (more risk genes = greater risk)

Question 74

SZ genes are also likely to interact with ___________

Answer 74

each other and/or with environmental risk factors

Question 75

Similar genes may be related to risk for other psychotic disorders, especially __________________

Answer 75

SZ spectrum and bipolar