Quiz 2 (Part of Lecture 7) Flashcards

1
Q

what are GWAS?

A

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

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2
Q

HapMap project

A

find markers all over the genome and associate them with diseases

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3
Q

What are the HapMap project’s uses?

A

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

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4
Q

HapMap has not done much for

A

the discovery of underlying causes of disease

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5
Q

Genome-wide association study is an

A

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

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6
Q

GWAS look at

A

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

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7
Q

what are SNPs?

A

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

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8
Q

How many SNPs have been identified?

A

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

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9
Q

Genetic variation in disease susceptibility; X chromosome recombination example

A
  • 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)
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10
Q

Genetic variation in disease susceptibility; Meta-analysis example

A
  • 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
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11
Q

SNPs in 6p21 region were linked to

A
  • 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
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12
Q

SNPs in 9p21 region were linked to

A
  • 10 unique diseases almost all of which were age-associated (ex. cancers, type 2 diabetes, glaucoma, and atherosclerotic diseases)
  • impacts repair mechanisms
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13
Q

The remaining 5 were directly linked to

A

immunity/inflammation or cellular senescence pathways (aging)

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14
Q

This analysis does not account for

A

SNP prevalence or scale of their effect

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15
Q

Human height is a trait

A

mainly determined by genes
heritability ~ 80%

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16
Q

GWAS height example

A
  • 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
17
Q

The GWAS height example suggests

A

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

18
Q

Male pattern baldness example

A
  • h2= 0.8
  • 71 loci were identified (30 previously unknown), explains 38% of the variation
  • MPB is less genetically complex than other traits
19
Q

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

A
  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
20
Q

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

A

metabolize drugs
- from gathering plant toxins

21
Q

Pharmacogenomics:

A

the impact of individual genetic variation on ability to metabolize drugs

22
Q

Serious sign in the late 1950s:

A

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

23
Q

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

A

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

24
Q

cytochrome p450s (CYP):

A
  • 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
25
CYP2D6 gene variation is clinically important because...
- 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)
26
The drug industry now tries to avoid
- 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
27
Impact on drug rehabilitation
genetic polymorphisms in CYP2B6 cause great individual variation in the dose of methadone needed to achieve blood concentration of the drug
28
n-Acetyl Transferases (NAT1 & NAT2)
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