Quiz 2 (Part of Lecture 7)

Question 1

what are GWAS?

Answer 1

genome-wide association studies
used to find genetic effects for common, chronic, and late-onset diseases where relative risks are lower and polygenic effects are common

Question 2

HapMap project

Answer 2

find markers all over the genome and associate them with diseases

Question 3

What are the HapMap project’s uses?

Answer 3

to describe common patterns of human genetic variation
to find genetic variants affecting health, disease, and responses to drugs and environmental factors

Question 4

HapMap has not done much for

Answer 4

the discovery of underlying causes of disease

Question 5

Genome-wide association study is an

Answer 5

observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait

Question 6

GWAS look at

Answer 6

hundreds of thousands of SNPs across a whole genome to see which of them are associated with a specific disease

Question 7

what are SNPs?

Answer 7

single nucleotide polymorphisms (SNPs) represent the substitution of a single base with another

Question 8

How many SNPs have been identified?

Answer 8

at least 50 million and can be found across the entire genome
- is used to ask questions about associations with specific diseases

Question 9

Genetic variation in disease susceptibility; X chromosome recombination example

Answer 9

• 2,000 individuals were examined for 7 diseases with 3,000 controls
• 24 significant association signals: 1 for bipolar, 1 for coronary heart disease, 9 for Crohn’s, 3 for rheumatoid arthritis, 7 for type 1 diabetes, and 3 for type 2 diabetes
• Some loci confer risk for more than 1 disease (pleiotrophy)

Question 10

Genetic variation in disease susceptibility; Meta-analysis example

Answer 10

• looked at 372 GWAS studies identifying 1775 SNPs associated with 105 unique human diseases (2.3 million individuals)
• 6p21 MHC locus: associated with immune function
• 9p21 INK4/ARF locus: not MHC locus but associated with disease

Question 11

SNPs in 6p21 region were linked to

Answer 11

• 24 unique diseases most of which were autoimmune in nature (ex. asthma, lupus, etc.)
• well established pathogenic role of MHC polymorphisms in the development of diverse autoimmune diseases

Question 12

SNPs in 9p21 region were linked to

Answer 12

• 10 unique diseases almost all of which were age-associated (ex. cancers, type 2 diabetes, glaucoma, and atherosclerotic diseases)
• impacts repair mechanisms

Question 13

The remaining 5 were directly linked to

Answer 13

immunity/inflammation or cellular senescence pathways (aging)

Question 14

This analysis does not account for

Answer 14

SNP prevalence or scale of their effect

Question 15

Human height is a trait

Answer 15

mainly determined by genes
heritability ~ 80%

Question 16

GWAS height example

Answer 16

• sample size 85,000 ppl
• 52 chromosomal regions that influence height identified (40 previously unknown)
• studies explained only about 3% of the variation in body height

Question 17

The GWAS height example suggests

Answer 17

that height is either influenced by almost the entire genome, or interactions among genes (epistasis) during development are very important, or both

Question 18

Male pattern baldness example

Answer 18

• h2= 0.8
• 71 loci were identified (30 previously unknown), explains 38% of the variation
• MPB is less genetically complex than other traits

Question 19

Why is the attempt to find the genetic determinants of disease not working that well?

Answer 19

1. common alleles almost never have large effects thus explain little of the variance in disease (1-2%)
2. Some missing causes may be found in rare alleles with large effects
3. The unexplained causation may be due to low-penetrance alleles
4. Much of the genetic causation may be missed because it is epistatic (interactions b/w alleles at different loci)
5. The genetic effects are probably masked by environmental effects

Question 20

Patients vary genetically in their ability to ____ ___ in part because of their evolutionary history

Answer 20

metabolize drugs
- from gathering plant toxins

Question 21

Pharmacogenomics:

Answer 21

the impact of individual genetic variation on ability to metabolize drugs

Question 22

Serious sign in the late 1950s:

Answer 22

an anti-diarrheal drug (clioquinol) tested and found safe on Europeans killed some Japanese

Question 23

Individual and interethnic variation in _____ and _____ was initially found through adverse drug reactions

Answer 23

cytochrome p450s (CYP) and n-acetyl transferases (NAT)

Question 24

cytochrome p450s (CYP):

Answer 24

• an ancient set of families of enzymes evolved by repeated gene duplications
• in humans, the 57 CYP genes are bound to the ER and inner mitochondrial membrane
• 23 genes account for about 75% of human drug metabolism

Question 25

CYP2D6 gene variation is clinically important because…

Answer 25

• now known to be involved in adverse reactions to or decreased drug effects of many drugs: antiarrhythmics, NEUORLEPTICS, antianginals, OPIOIDS, AMPHETAMINES, and anticancer drugs
• can be genetically predisposed to addiction bc of this enzyme
• the percentage of poor metabolizers (PM) varies strikingly among ethnic groups
• can vary from 2 to 13 copies per individual (duplications reduce the efficacy of drugs)

Question 26

The drug industry now tries to avoid

Answer 26

• developing drugs that are metabolized by CYP2D6 because they cannot predict how individuals will react to it
• CYP2D6 metabolized 25% of drugs on the market

Question 27

Impact on drug rehabilitation

Answer 27

genetic polymorphisms in CYP2B6 cause great individual variation in the dose of methadone needed to achieve blood concentration of the drug

Question 28

n-Acetyl Transferases (NAT1 & NAT2)

Answer 28

these enzymes activate and deactivate both drugs and carcinogens in the liver cytosol
- different alleles combine to produce rapid, intermediate, and slow acetylator phenotypes
they metabolize drugs including sulfonamides, many other drugs, and metabolites of caffeine
- Europeans & North Americans are 22-26% fast acetylators
- East Asians are 67-74% fast acetylators