Genetic Epidemiology

Question 1

What is genetic epidemiology?

Answer 1

• study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors
• seeks to derive a statistical and quantitative analysis of how genetics work in large groups
• population dynamics alter the frequency and distribution of both genetic and environmental factors and thus their net effect on the phenotype of interest; gene pool in Canada evolves constantly, environment evolves (eg. cell phones), and as a result the findings we make at time t are not necessarily applicable to t plus 10 years

Question 2

What is a genome?

Answer 2

-entire DNA of a species

Question 3

Describe DNA composition and human genome

Answer 3

• A, G, T, C nucleotides
• DNA is double helix (A-T or C-G attached to sugar phosphate backbone)
• 3.2 million base pairs
• human genome is diploid; two DNA copies inherited from two parents
• 22 autosomal and 1 sexual chromosome pairs (women XX, men XY)

Question 4

What is a gene?

Answer 4

• specific sequence that is transcribed into mRNA and translated to protein, and controls expression of traits
• 19000/20000 genes
• 2% coding, 98% not coding
• range from <1000 to >1000000 base pairs
• 99.9% of DNA sequence is identical in all humans

Question 5

What are types of genetic variations?

Answer 5

Inversions: chunk of DNA inversed

Translocations: chunk of chromosome go on another chromosome (no loss of genetic info)

Fusions: relatively rare, chromosome becomes a ring and the telomeres stick together- functions the areas that stick together but the other genes in the ring are functional (growth is impacted)

Deletions: portion of chromosome that disappears

Duplications: 3 copies of the gene (compared to normal having 2 copies one from each parent)

Short/variable number-tandem repeats

Insertion: few base pairs are inserted but can mess up amino acid coding if its in a coding region

Single nucleotide variants: no structural variation, just variation in the sequence (accounts for 90% of human genetic variation)

Question 6

What is an allele? What are the combinations of different alleles?

Answer 6

• state at a specific marker
• homozygous: 2 copies of same allele
• heterozygous: 2 different alleles
• haplotype: sequence of alleles along one chromosome (neighbouring mutations that are inherited)

Question 7

What results from non-synonymous mutation (mutation leading to amino acid change)?

Answer 7

-50% has no effect on protein, 40% makes it less functional or not functional at all, 10% it increases function

Question 8

When can a mutation in the coding region not have negative consequences? When does it impact amino acid structure of protein?

Answer 8

• can have a mutation but it doesn’t change the amino acid
• eg. your parents have TCT base pair combination, and you have a mutation of TCC but these both code for serine
• if there is a mutation that changes TAC into TAA, TAC leads to tyrosine but TAA is a stop codon so this will stop amino acid production and can lead to protein not being made

Question 9

What is new regarding the intergenic region?

Answer 9

• geneticists usually interested in the coding region because it has the potential to change the structure of the protein and result in disease with mutations
• more recently people are realizing that there is a lot of gene regulation happening in intergenic region having an impact on other genes down further

Question 10

What are linkage disequilibrium blocks?

Answer 10

• if you knew mutation 1, you could predict the allele for 100, etc. other mutations because they are always inherited together
• linkage disequilibrium is the non-random association of alleles at two or more loci
• human genome is composed of blocks of linkage disequilibrium
• extent of linkage disequilibrium blocks varies according to ethnic background
• areas of DNA that are most likely for mutation; as a result you have sections of DNA that are the same as your first ancestor

Question 11

What are explanations for why the African population has smaller blocks of correlation between mutations compared to the European population that has large blocks of mutations inherited together?

Answer 11

• African population had more generations than the others (hypothesis that the human species started in Africa)
• they are more ancestral population so they have more opportunity to redistribute the DNA
• only 2 are coinherited together compared to 4 in the European population

Question 12

What is inherited versus de novo genetic variation?

Answer 12

• most genetic variation we get from our parents; inherited
• de novo: DNA replication accidents (DNA repair methods are highly sophisticated but sometimes there is a de novo mutation that escapes attention of DNA polymerase)
• sometimes this happens at the cellular level and can lead to areas of the body having the mutation and some areas not having it
• de novo mutations can happen from reactive cellular metabolites, chemicals, radiation

Question 13

What is a phenotype? What are important things about a phenotype?

Answer 13

• set of observable characteristics of an individual resulting from the interaction of its genotype with the environment
• can be a disease (endpoint), intermediary trait (appetite, physical activity, etc)
• binary (disease or no), categorical (smoker/non smoker), or quantitative (weight)
• clinically and biologically relevant
• easy and inexpensive to measure
• relevant in diverse ethnic groups
• minimal measurement error
• minimal misclassification and reporting biases
• heritable

Question 14

How do we know if a trait is an heritable condition? How can it be studied?

Answer 14

• heritability: proportion of the total variation between individuals for the given trait in a given population that is explained by genetic factors
• between 0 and 100%
• if you have a heritability of 50%, 50% of the risk of disease/genetic variation is explained by genetic factors
• can be studied in twins, families, general population

Question 15

How are traits compared in twins?

Answer 15

• compare the correlation between variable in identical twins and fraternal twins
• the difference in this correlation represents 50% of genome

Question 16

How are genetic variations studied in families?

Answer 16

• compare correlation of trait between siblings and between offspring and parents
• share 50% of genome with dad and 50% of genome with mom
• 50% of genetic similarity with sibling
• compare parent/offspring correlation and sibling correlation with the correlation of the trait between spouses
• usually genetic similarity between spouses is 0

Question 17

When would you do a study about BMI?

Answer 17

• heritability at age 4 of BMI is 0.48
• heritability at age 11 of BMI is 0.78
• do the study with kids at age 11 because the genes have more impact then

Question 18

What contributes to phenotypic variation?

Answer 18

• genetics
• environment

Question 19

What are different types of traits?

Answer 19

• 100% genetic; Mendelian genetics (syndromic monogenic- very rare and is accompanied by other things such as 6 fingers/toes, mental retardation, non-syndromic monogenic/oligogenic accompanied by extreme appetite)
• oligogenic means there are some environmental factors as well
• polygenic: multiple genetic variants with modest effects and these are widespread in the population
• 100% environmental (eg. sumo fighter is environmentally obese because of 5 meals a day)
• interaction of genetic and environmental factors

Question 20

What is autosomal dominant?

Answer 20

-one mutation is sufficient to develop the disease

Question 21

What is autosomal recessive?

Answer 21

• need 2 bad copies of the gene to develop the disease
• both parents don’t have the disease
• each parent has 1 bad copy of the gene and so the probability is that 25% of the time the kid will get both bad copies from parents to develop the disease

Question 22

What is x-linked recessive?

Answer 22

• in women, need to have 2 bad copies of X
• because men only have one copy of X, if they have one copy of the bad X then they will develop the disease

Question 23

What is mitochondrial inheritence?

Answer 23

-transmitted mainly by mom

Question 24

What are the common study designs for genetic discoveries?

Answer 24

• case control studies (good for rare disorders)
• quantitative trait studies (in whole population-eg. studying body weight- acquire genetic information for a population and try to identify genetic variants that are correlated to differences in body weight)
• family-based association studies: study transmission of mutations across generations and how it correlates with the disease (useful for rare mutations)
• cohort studies: correlation of a genotype with an incident disease event (gold standard in observational epidemiology). In genetic epi, cross sectional studies are easier.
• exposure to genes always preceds the collection of data so not as exciting to have longitudinal studies in genetics because everything is essentially prospective
• clinical trials, intervention studies: correlation of a genotype with response to intervention or treatment

Question 25

Is it best to study the general population or extreme phenotypes when identifying genetic factors?

Answer 25

- people with extreme phenotype are rich in genetic factors - if you have access to general population, study body weight in the general population as a continuous trait - also design a case control study to study genetic factors in extreme phenotype- may identify genes here that you have missed in the general population design

Question 26

How does identifying genes translate into applications for healthcare?

Answer 26

- better idea about biological mechanism leading to disease - identify molecular targets for the development of novel predictive biomarkers or drugs - to identify people at high risk for the disease - to provide personalized prevention for high risk people - to provide tailored treatment for high-risk people

Question 27

What are monogenic/oligogenic obesity treatments?

Answer 27

- congenital leptin deficiency; give leptin therapy - setmelanotide is agonist of MC4R receptor (still in leptin pathway)- mutation here semelanotide is considered for treatment