1. Beginning of the chapter Simple disease risk statistics 16

2. GENETICS Disease risk statistics

3. GENETICS How do we know the risk? Concept: Odds Ratio The risk of developing a disease due to a genetic variation Example: G = Functional gene (wild type) A = Mutated gene (mutant) Diabetes gene

4. GENETICS Everyone has two genes of each type (with a few exceptions) A genetic variation may therefore occur on both, or only on one gene Example: The possible outcomes are: G on both genes>> G/G >> Wild type G on one, A on the other gene >> G/A >> Heterozygous A on both genes >> A/A >> Homozygous mutant G = Functional gene (wild type) A = Mutated gene (mutant) How do we know the risk? GG GA AA

5. GENETICS How do we know the risk? GGGAAA G/G A/GA/GA/GA/GA/A Wild type Heterozygous Homozygous mutant The 3 possibilities: OR:1OR:2 OR:4 Normal risk of developing the disease DOUBLE risk of developing the disease QUADRUPLE risk of developing the disease

6. GENETICS How do we know the risk? OR = 1.65 1.65-times risk of developing the disease 65% higher risk

7. GENETICS How do we know the risk?

8. GENETICS How does the OR influence the probability of developing a disease? Example DEMO SYNDROME (very rare): 1 risk gene variant exists (just an example) General population has “normal” risk (population average: OR = 1) 1 out of 100 000 suffers from the disease, 0.001% lifetime risk ODDS RATIO relative to the POPULATION AVERAGE (ORpop): Population average:ORpop = 1 Example OR for a woman: ORpop = 60 PROBABILITY OF DEVELOPING THE DISEASE Average = 0.001% lifetime risk = 0.001% probability of developing the disease for ORpop = 1 What is the PROBABILITY OF DEVELOPING THE DISEASE for ORpop = 60? = 0.06% probability of developing the disease

9. GENETICS How does the OR influence the probability of developing a disease? Although with genetic variations the risk is 60 times higher, the probability of developing the disease is only 0.06% This genetic analysis is not relevant for health!

10. GENETICS Examples of genetic influence on diseases The disease occurs in approx. 5% of the population, genetic variations increase the risk to OR = 7 >> probability of developing the disease increases from 5% to 30% RELEVANT! The disease occurs in approx. 1%, genetic variations increase the risk to OR = 1.1 >> probability of developing the disease from 1% to 1.1% NOT RELEVANT! The disease occurs in approx. 1%, genetic variations increase the risk to OR = 60 >> probability of developing the disease from 1% to 45% RELEVANT! The disease occurs in approx. 0.001%, genetic variations increase the risk to OR = 90 >> probability of developing the disease from 0.001% to 0.06% NOT RELEVANT! The disease occurs in approx. 0.001%, mutations lead to developing the disease in all cases >> probability of developing the disease from 0.001% to 100% RELEVANT!

11. GENETICS Why is the OR used for genetic analyses, instead of the probability of developing the disease? OR 3 ALZHEIMER'S RISK PREVENTION PROGRAM UNHEALTHY LIFESTYLE OR 0.36 OR 0.6OR 1.4 3 x 0.36 x 0.6 = 0.64 OR Disease probability 13.46% 3 x 1.4 = 4.2 OR Disease probability 60.82% Disease probability average: 20%

12. GENETICS Summary: The genetic risk is stable and unchangeable. Different analyses of the same genes should yield the same OR, even when conducted by different laboratories. The disease probability is affected by Positive (OR smaller than 1) and Negative (OR bigger than 1) environmental influences. Thus, the probability of disease cannot be reliably measured in the laboratory. Why is the OR used for genetic analyses, instead of the probability of developing the disease?

13. GENETICS The aim of preventive genetic analysis: To predict the probability of developing a disease! To positively influence the risk of developing the disease! Why is the OR used for genetic analyses, instead of the probability of developing the disease?

14. End of the chapter Simple disease risk statistics 16