Genetic Epidemiology Flashcards

1
Q

What is genetic epidemiology?

A
  • 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
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2
Q

What is a genome?

A

-entire DNA of a species

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3
Q

Describe DNA composition and human genome

A
  • 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)
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4
Q

What is a gene?

A
  • 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
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5
Q

What are types of genetic variations?

A

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)

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6
Q

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

A
  • 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)
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7
Q

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

A

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

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8
Q

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

A
  • 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
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9
Q

What is new regarding the intergenic region?

A
  • 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
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10
Q

What are linkage disequilibrium blocks?

A
  • 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
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11
Q

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?

A
  • 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
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12
Q

What is inherited versus de novo genetic variation?

A
  • 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
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13
Q

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

A
  • 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
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14
Q

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

A
  • 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
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15
Q

How are traits compared in twins?

A
  • compare the correlation between variable in identical twins and fraternal twins
  • the difference in this correlation represents 50% of genome
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16
Q

How are genetic variations studied in families?

A
  • 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
17
Q

When would you do a study about BMI?

A
  • 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
18
Q

What contributes to phenotypic variation?

A
  • genetics
  • environment
19
Q

What are different types of traits?

A
  • 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
20
Q

What is autosomal dominant?

A

-one mutation is sufficient to develop the disease

21
Q

What is autosomal recessive?

A
  • 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
22
Q

What is x-linked recessive?

A
  • 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
23
Q

What is mitochondrial inheritence?

A

-transmitted mainly by mom

24
Q

What are the common study designs for genetic discoveries?

A
  • 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
25
Q

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

A
  • 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
26
Q

How does identifying genes translate into applications for healthcare?

A
  • 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
27
Q

What are monogenic/oligogenic obesity treatments?

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