L11 Genetic epidemiology

Question 1

Define genetic epidemiology.

Answer 1

Genetic epidemiology is the study of the aetiology, distribution and control of disease in groups of relatives and of inherited causes of disease in populations.

Or

The 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.

Question 2

What is the purpose of genetic epidemiology?

Answer 2

To uncover the role of genetic factors in determining health and disease through the detection of inheritance patterns and localization of the gene associated with disease.

Question 3

What is genetic epidemiology useful for? (5)

Answer 3

• Defining the genetic contribution to a disease or disorder (if there is one)
• Establishing risk estimates
• Increasing our understanding of disease mechanisms
• Identifying new targets for intervention and the development of new treatments
• Learning more about the impact of the environment and lifestyle on disease by using genes as ‘surrogates’ for these exposures

Question 4

Read

What is a gene?

• The molecular unit of heredity
• Composed of stretches of DNA sequence including regulatory regions & coding regions
• Coding regions are transcribed & translated into proteins
• Two copies (alleles)
• We have around 25,000 (2-3%) of the human genome

Question 5

List the objectives of genetic epidemiology. (3)

Answer 5

1. Establishing a genetic component
2. Establishing the size of the genetic effect in relation to other factors implicated in disease risk (i.e. environmental effects).
3. Identifying the gene(s) responsible for the genetic component.

Question 6

Define a linkage disequilibrium.

Answer 6

Non-random association of two or more alleles.

Question 7

Define haplotype.

Answer 7

A set of SNPs on a single chromatid of a chromosome pair that are statistically associated.

Question 8

Define haplotype blocks.

Answer 8

Sizeable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed.

Question 9

Read

Genome-wide association studies

• The examination of many common genetic variants (SNPs, typically >500,000) in a group of individuals (typically 1,000’s) to see if any variant is associated with a trait
• The 1st GWAS was conducted in 2005 and compared 96 patients with age-related macular degeneration with 50 healthy controls
• Recent GWAS of body mass index reported data on 250,000 individuals
• Consortia are commonly established to pool data and resources (GIANT, EAGG, EAGLE, GABRIEL etc.)

Question 10

Read

The future of genetic epidemiology: Predicted developments (next 5-10 years)

• Identification of genetic factors affecting disease prognosis
• Understanding the genetic contribution to intermediate phenotypes linking genes and disease
• Understanding the contribution of ‘new’ aspects of genetics; copy number variation, epigenetics, rare variants
• Clarification of known genes with disease to refine risk estimates
• Using genes as tools to better understand the influence of the environment and lifestyle in disease processes
• Large scale population-based genomics projects generating data on an unprecedented scale

Question 11

In Recurrence risk, the higher the value of lambda, the what?

Answer 11

The stronger the genetic effect.

Examples (lambda)

Alzheimer Disease 3-4

Rheumatoid Arthritis 12

Schizophrenia 13

Type I Diabetes 15

Multiple Sclerosis 20-30

Neural Tube Defects 25-50

Autism 75-150

Question 12

What is Familial Aggregation for a disease measured in? (2)

Answer 12

• Relative recurrence risk (RRR)
• Familial risk ratios (FRRs)

Question 13

State the equation of recurrence risk.

Answer 13

lambda_R = k_R / k

where:

k_{<strong>R</strong>} is the risk to relatives of type R

k is the population risk

R denotes a relationship (e.g. S=sibling, O=offspring)

lambda_R is the recurrence risk of relations compared to general population

Question 14

No change in disease risk following migration is indicative of ______ determinants.

Answer 14

Genetic

Question 15

Twin studies:

• Comparison of monozygotic (MZ) pairs (who share ___1___ of their genes) with dizygotic (DZ) twins (who share ___2___ of their genes in common).
• The ___3___ similarity of MZ twins than DZ twins is considered evidence of genetic factors

Answer 15

1. All
2. Half
3. Greater

Question 16

Question 17

Question 18

Question 19

Define the differences in Linkage and Association studies.

Answer 19

Linkage studies

• Used mainly in the study of single gene disorders
• Use genetic markers situated throughout genome. These markers will generally not be functionally significant
• Use extended families, or in certain types of study, cases and unrelated controls
• Linkage for a genetic marker to disease may be unique to the particular family

Association studies

• Used to identify genes involved in polygenic disorders
• Use cases and appropriately matched controls who are normally unrelated
• Association of a genotype with disease is a statistical finding which usually requires investigation of the functional relationship

Question 20

Question 21

Define concordance with regards to genotyping (SNP) studies.

Answer 21

A measure of the percentage of SNPs that are measured as identical between 2 individuals.