Genetics of Common Diseases III Flashcards
What do GWA studies point to?
regions of association with a disease phenotype, but in most cases not to the genes involved.
problems about variants identified by GWAs
it is hard to find functionally relevatn gene.
Contribution to disease etiology questionable
low penetrance
many SNPs identified by GWAs wwere not close to any genes and even in areas called gene deserts with no genes within millions of base pairs.
whre most SNPs are located
in non-protein coding DNA sequences
where most GWA SNPs are located
in or near regulatory sequences.
most GWAs are caused by
changes in gene regulation rather than changes to the proteins produced by genes.
most common diseases and traits are _
polygenetic, i.e. a large number of underlying genetic variants affect the disease or trait.
Although GWAs hav implicated hundreds of new loci in common complex disease,
most of the identified variants have a small effect on risk and they collectively explained only a fraction of disease heritability.
GWAs suggest that
heritability in common diseases may not only be due to common variants.
rare variants
not studied by GWAs
require sequencing
exome sequencing
possible because of reduced cost and time for sequencing, especially exome sequencing.
CDRV hypothesis
common disease is due to the aggregate contribution of multiple different rare variants rather than only common varients.
example of the CDRV hypothesis
they explained the 1.7% of the heritable variation in adult height.
Threschold model of common disease
A certain combination of genetic (common and rare variants) and environmental factors are needed in order for a person to affected with a multifactorial condition.
the genetic and environmental factors add together and, when they reach the threshold level, cause a person to be affected.
• General rule: rare variants in __, common variants in__.
• General rule: rare variants in protein coding, common variants in regulatory sequences
