Quiz 2 (Part of Lecture 7) Flashcards
what are GWAS?
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
HapMap project
find markers all over the genome and associate them with diseases
What are the HapMap project’s uses?
to describe common patterns of human genetic variation
to find genetic variants affecting health, disease, and responses to drugs and environmental factors
HapMap has not done much for
the discovery of underlying causes of disease
Genome-wide association study is an
observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait
GWAS look at
hundreds of thousands of SNPs across a whole genome to see which of them are associated with a specific disease
what are SNPs?
single nucleotide polymorphisms (SNPs) represent the substitution of a single base with another
How many SNPs have been identified?
at least 50 million and can be found across the entire genome
- is used to ask questions about associations with specific diseases
Genetic variation in disease susceptibility; X chromosome recombination example
- 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)
Genetic variation in disease susceptibility; Meta-analysis example
- 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
SNPs in 6p21 region were linked to
- 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
SNPs in 9p21 region were linked to
- 10 unique diseases almost all of which were age-associated (ex. cancers, type 2 diabetes, glaucoma, and atherosclerotic diseases)
- impacts repair mechanisms
The remaining 5 were directly linked to
immunity/inflammation or cellular senescence pathways (aging)
This analysis does not account for
SNP prevalence or scale of their effect
Human height is a trait
mainly determined by genes
heritability ~ 80%
GWAS height example
- 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
The GWAS height example suggests
that height is either influenced by almost the entire genome, or interactions among genes (epistasis) during development are very important, or both
Male pattern baldness example
- h2= 0.8
- 71 loci were identified (30 previously unknown), explains 38% of the variation
- MPB is less genetically complex than other traits
Why is the attempt to find the genetic determinants of disease not working that well?
- common alleles almost never have large effects thus explain little of the variance in disease (1-2%)
- Some missing causes may be found in rare alleles with large effects
- The unexplained causation may be due to low-penetrance alleles
- Much of the genetic causation may be missed because it is epistatic (interactions b/w alleles at different loci)
- The genetic effects are probably masked by environmental effects
Patients vary genetically in their ability to ____ ___ in part because of their evolutionary history
metabolize drugs
- from gathering plant toxins
Pharmacogenomics:
the impact of individual genetic variation on ability to metabolize drugs
Serious sign in the late 1950s:
an anti-diarrheal drug (clioquinol) tested and found safe on Europeans killed some Japanese
Individual and interethnic variation in _____ and _____ was initially found through adverse drug reactions
cytochrome p450s (CYP) and n-acetyl transferases (NAT)
cytochrome p450s (CYP):
- 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
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)
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
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
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
