W9LECT - Complex inheritance Population genetics

Question 1

What is The role of genes and environmental factors in the development of diseases?

Answer 1

• a polygenic trait reflects the activities of more than one gene.
• Both single-gene and polygenic traits can also be multifactorial, which means they are influenced by the environment

Question 2

What are the differences between early onset and late onset Alzheimer’s disease?

Answer 2

Question 3

Frequency of diseases with genetic background
-> Identify

Answer 3

1. Polygenic
2. Oligogenic
3. Monogenic

Question 4

Which are the most frequent diseases?

Answer 4

Question 5

What are the 2 types of Multifactorial diseases?

Answer 5

1. Congenital malformations
2. Chronic adult diseases:

Question 6

What are the examples of Congenital malformations?

Answer 6

dislocation of hip, neural tube defects, cleft lip and/or palate, microcephaly

Question 7

What are the examples of Chronic adult disease?

Answer 7

Cancer, Diabetes type II, Hypertension, asthma, atherosclerosis (coronary), rheumatoid arthritis, multiple sclerosis, epilepsy, schizophrenia, Parkinson disease, manic depression

Question 8

Can traits be continuous?

Answer 8

YES! TRAITS can be CONTINUOUS
= quantitative trait
= varies along a continuum

Question 9

What are the 5 predictions of the multifactorial threshold model?

Answer 9

1. Recurrence risks represent average risks and will vary among different families.
2. The risk increases with the number of affected relatives.
3. The risk increases with the severity of the malformation or disease.
4. The differential risk to relatives of an affected proband increases as the frequency of the disease or malformation in the general population decreases.
5. When the sex ratio of affected probands deviates

Question 10

I. Methods to determine Complex inheritance
1. What are the method to determine Complex inheritance?

Answer 10

1. Family study
2. Family-based association studies
3. Accumulation within a family
4. Concordance and disconcordance
5. Twin studies

Question 11

I. Methods to determine Complex inheritance
2. How do we use family study to determine complex inheritance?

Answer 11

1. Provides estimates of the degree of family aggregation
2. Risks to siblings, parents, offspring as well as to other relatives can be estimated
3. Similarity of different types of relatives can permit modelling of genetic versus non-genetic familial influences

Question 12

I. Methods to determine Complex inheritance
3. How can heritability be studied?

Answer 12

Comparing frequency within the family with that of the entire population

Question 13

I. Methods to determine Complex inheritance
4. Give examples of Risk Ratios for Siblings of Probands with Complex Diseases with Familial Aggregation

Answer 13

Question 14

I. Methods to determine Complex inheritance
5. How is diabetes inherited?

Answer 14

MODY (autosomal dominant)
(GCK, HNF-4 alpha and HNF-1 alpha mutations)

Question 15

I. Methods to determine Complex inheritance
6. Describe Family-based association studies

Answer 15

Question 16

I. Methods to determine Complex inheritance
7. How do we determine Accumulation within a family?

Answer 16

frequency of the disease among siblings/ frequency of the disease in the entire

Question 17

I. Methods to determine Complex inheritance
8. How do we give Estimation of heretability by Twin studies?

Answer 17

Question 18

I. Methods to determine Complex inheritance
9. What are Concordance and disconcordance?

Answer 18

The degree of concordance is the degree of similarity between two individuals
– If both twins carry the disease, they are concordant
– If only one twin carries it, they are disconcordant

Question 19

I. Methods to determine Complex inheritance
10A. How do we calculate Concordance?

Answer 19

• Calculated as the number of twin-pairs with disease amongst those twin-pairs with at least one affected twin (Gordis):
  #twins with both affected
  (# twins with both affected + # twins with only one affected)

Question 20

I. Methods to determine Complex inheritance
10B. What happen if Concordance < 100% in MZ twins?

Answer 20

Concordance < 100% in MZ twins is evidence for nongenetic etiological factors.

Question 21

I. Methods to determine Complex inheritance
10C. What happen if Concordance in MZ twins > DZ twins?

Answer 21

Concordance in MZ twins > DZ twins is evidence for genetic etiological factors.

Question 22

I. Methods to determine Complex inheritance
10D. What are Concordance Rates in MZ and DZ Twins in case of DIABETES?

Answer 22

Question 23

I. Methods to determine Complex inheritance
11. What are differences between monozygotic and dizygotic twins?

Answer 23

• To form identical or monozygotic twins, one fertilised egg (ovum) splits and develops into two babies with exactly the same genetic information.
• To form fraternal or dizygotic twins, two eggs (ova) are fertilised by two sperm and produce two genetically unique children.

Question 24

I. Methods to determine Complex inheritance
12. Genes or shared family experiences?

Answer 24

1. To disentangle genes and experience, we study special family groups
2. Either family members sharing experiences but differing in shared genes, e.g. twin studies or
3. family members sharing genes, but differing in their shared experience, e.g. adoption studies

Question 25

I. Methods to determine Complex inheritance 13. How can we investigate environmental factors based on studies on adopted children?

Answer 25

1. Strong concordance with the biological parents -> the disease has strong genetic background 2. Strong concordance with adopting parents -> environment is decisive

Question 26

I. Methods to determine Complex inheritance 14. Describe Worldwide prevalence of obesity

Answer 26

- prevalence of obesity nearly tripled between 1975 and 2020 - in 2020, more than 2 billion adults were overweight , over 600 million were obese - In Europe, more than half the population is overweight => This makes it the first generation predicted to have a shorter lifespan than their parents

Question 27

I. Methods to determine Complex inheritance 15. Why is it important to research the genomic background of multifactorial diseases?

Answer 27

1. Molecular pathomechanimus 2. Personalized treatment 3. Screening people , genetic predisposition

Question 28

I. Methods to determine Complex inheritance - Difficulties in phenotyping 16. What are Difficulties in phenotyping?

Answer 28

– Many times there is no standard diagnosis. – The clinical picture may change with age – Symptoms may occur in episodes – Otherillnesswithsimilarsymptoms – Different diseases often occur together ( comorbidity ).

Question 29

I. Methods to determine Complex inheritance - Difficulties in phenotyping 17. What is QT: quantitative trait?

Answer 29

- A characteristic that can be defined by a number. - Eg: LDL-C, blood pressure, IgE level, BMI

Question 30

I. Methods to determine Complex inheritance - Difficulties in phenotyping 18. What is QTL: quantitative trait locus?

Answer 30

a locus that segregates with a given feature .

Question 31

I. Methods to determine Complex inheritance 19. What are Hypotheses for obesity?

Answer 31

There are genetic variants, which gave earlier a selection advantage, but in our days they make us susceptible to certain diseases.

Question 32

I. Methods to determine Complex inheritance 20. What is Thrifty gene hypothesis?

Answer 32

1. Thrifty genes enable individuals to efficiently collect and process food to deposit fat during periods of food abundance. 2. Fatter individuals carrying the thrifty genes would thus better survive times of food scarcity. 3. In modern societies with a constant abundance of food, this genotype efficiently prepares individuals for a famine that never comes. 4. an absence of selection, combined with genetic drift

Question 33

I. Methods to determine Complex inheritance 21. What is Hypotheses for cariovascular diseases?

Answer 33

There are genetic variants, which gave earlier a selection advantage, but in our days they make us susceptible to certain diseases.

Question 34

I. Methods to determine Complex inheritance 22. What are the features of Salt-conserving phenotype?

Answer 34

1. Earlier it was advantageous, if the salt-loosing was kept minimal especially for populations living in warm climate. 2. In our days when salt is abundant this genetic background leads to a higher susceptibility to salt sensitive hypertension.

Question 35

I. Methods to determine Complex inheritance 23. State Antagonistic pleiotropy hypothesis

Answer 35

- Variants, which are advantageous in younger age, but harmful in older - It is called antagonistic pleiotropy => The stronger inflammatory response can be advantageous in younger age, but harmful in older, because chronic diseases in old age are often inflammatory, like atherosclerosis, rheumatoid arthritis or Alzheimer disease.

Question 36

II. Population genetics 1. What is population?

Answer 36

A population is a group of individuals of the same species who share a geographic area and usually mate within the group

Question 37

II. Population genetics 2. What is gene pool?

Answer 37

The total genetic variation of that population is the gene pool

Question 38

II. Population genetics 3. What is frequency?

Answer 38

The total genetic variation of that population is the gene pool

Question 39

II. Population genetics 4. What is evolution?

Answer 39

evolution is the change in allele frequency over generations

Question 40

II. Population genetics 5. How do we give Evaluation of population genetic studies?

Answer 40

- SNVs: binary: usually two nucleotides in one locus (eg A / G; p and q ) - Genotype: 3 (eg AA; AG; GG) - MAF: minor allele frequency

Question 41

II. Population genetics - Hardy-Weiberg 6A. Give the equations of Hardy-Weiberg

Answer 41

Question 42

II. Population genetics - Hardy-Weiberg 6B. What are Major Allele Frequency (p) and Major Allele Frequency (q)?

Answer 42

- The most common allele would be known as the major allele and its frequency would be the Major Allele Frequency (p) - Minor Allele Frequency (q) refers to the frequency of the second most common of the two alleles present.

Question 43

II. Population genetics - Hardy-Weiberg 7. For a given autosomal recessive disease, q = 0.01 (where q is the allele frequency of the mutant allele). Approximately what percentage of the population has two copies of the normal allele?

Answer 43

Question 44

II. Population genetics - Hardy-Weiberg 8. Describe Association studies (heart disease)

Answer 44

Question 45

II. Population genetics 9. What are the 2 types of sample collection?

Answer 45

1. Retrospective study 2. Prospective study

Question 46

II. Population genetics 10. What are the features of Retrospective study?

Answer 46

A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study

Question 47

II. Population genetics 11. Explain p value

Answer 47

1. Def: What is the probability of a false association? 2. The significance limit is usually p = 0.05: chance of error (type I error): – We can be wrong once in 20 3. If many tests are performed (eg GWAS) the probability of a false association increases: it must be corrected by the number of tests: Bonferroni correction: – p = 0.05 / number of tests

Question 48

II. Population genetics 12. How do we use Risk calculation?

Answer 48

1. OR=oddsratio.Use:retrospective studies. 2. RR = relative risk : use: prospective studies. 3. If the OR or RR > 1, the allele increases the risk of the disease 4. <1reduces

Question 49

II. Population genetics 13. Give an example of Retrospective study

Answer 49

Question 50

II. Population genetics 14. What are Problems with retrospective studies?

Answer 50

1. Relationship between environmental effects and disease: difficult to find relationship 2. Those who have died and mild patients may be eliminated

Question 51

II. Population genetics 15. What are features of Prospective study?

Answer 51

- A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). - where participants are enrolled before any of them have the disease or outcome being investigated.

Question 52

II. Population genetics 16. What are Results of Genetic Approaches to the Common Diseases?

Answer 52

- Genetic variants associations (eg: ApoE4 in Alzheimer disease) - New pathomechanism (reduced insulin secretion: MTNR1B, TCF7L2, KCNJ11in T2DM - Personal predisposing gene set (BRCA1, BRCA2)

Question 53

III. Polygenic Risk Score 1. How do we calculate polygenic risk score?

Answer 53

- The enormous amount of genomic data now available enables researchers to calculate which variants tend to be found more frequently in groups of people with a given disease. There can be hundreds or even thousands of variants per disease. - Researchers put this information into a computer and use statistics to estimate how the collection of a person’s variants affect their risk for a certain disease. => This yields polygenic risk scores. => All of this can be done without knowing the specific genes involved in the complex disease. While we may someday know all the genes involved, researchers can estimate risk now without this link.

Question 54

III. Polygenic Risk Score 2. What are the characteristics of The potential genetic variants?

Answer 54

1. must be truly associated with the health condition or its measure, so that it can be used as a proxy for exposure of interest 2. it should not be associated with measured/unmeasured confounders of the exposure-outcome relation, 3. Exclusion restriction criteria, i.e., the instrument/genetic variant should not be directly associated with the outcome and its effect must be mediated only through the exposure => implying that no alternative causal pathway exists between instrument and outcome except via exposure => Mendelian randomization

Question 55

III. Polygenic Risk Score 3. What is the role of mendelian randomization?

Answer 55

assessing causal association of genetic variant which acts as a proxy for modifiable biological traits, with outcomes related to health economics.

Question 56

III. Polygenic Risk Score 4. There is One study examined causal association between child's/adolescent's height and - cognitive - mental health - behavioral outcomes like academic carrier IQ - self-esteem - depression symptoms behavioral problems By using genetic determinants of height => What can we conclude from mendelian randomization?

Answer 56

Height presents disadvantage rather than advantage as it was fund to increase hyperactive behaviour among girls and emotional and peer problems among boys.

Question 57

Give examples of Genomewide investigations

Answer 57

Genomewide GWAS, CGH, NGS investigations

Question 58

How do we Investigat3 of susceptibility genes

Answer 58

in linkage and target gene association studies

Question 59

. Environmental effects can be investigated by ___ (3 things)

Answer 59

adoption, migration and epidemiology studies