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used GWA and found mixed success, why?
most variants had low odds ratios.
and SNPs were intergenic and intronic, suggesting a greater role for noncoding SNPs in common diseases.

it wouldnt tell u enough about the Pt to make it worth while for the Pt.
eventhough complex diseases don't have mendelian inheritance, they have a higher risk.
what were some problems with GWA studies?

another thing is that they narrowed it down to 2 genes but still didnt know which one.
The SNP found was associated with a disease, may be FAR from any known genes.

The SNPs so far from GWAs studies only explain a small fraction of the burden of the disease.

there is a super sized list of obesity genes.

at present, the observed genetic variation for obesity explains only 1% of the total genetic variation present in the population
suggesting that many many genes would have to be involved in obesity.
ENCODE discovered that most SNPs were found in...
most SNPs were found in noncoding protein sequences

most were in or near regulatory DNA sequences

this explains why the odds ratio is low and why a SNP found far from a gene can still be associated with the gene. (because regulatory elements dont have to be near genes. they can be millions of pairs away, but work thru chromosome looping)

thus the SNPs are controlling the regulatory elements instead of the genes themselves.
a large number of SNP variants were identified for each common disease. what were the problems associated with variants identified by GWAs?
individually, each identified variant makes a small contribution to the overall susceptibility of a disease.

It is often hard to find functiionally relevant genes.

The contribution to disease of each gene is questionable.

Low penetrance.

Many SNPs identified by GWAs were not close to any genes and some are even in areas called gene deserts with NO genes within millions of BPs.
Missing heritability-
GWA studies did not identify SNPs in genes with huge contributions to heritability. THese results suggested that heritablilty in common diseases may not only be due to common variants. Thus scientists started to study
rare variants
although GWAs have provided valuable insight into genetic basis of human disease, they have explained little of the heritability of most complex traits, and the variants discovered have small effect sizes. this has led to the issue of where the 'missing heritability' of complex diseases may be found.
A hypothesis is that the missing hereditablity was due to
rare genetic variants
why is the odds ratio low in complex diseases?
in complex diseases they have low odds ratio because most of the SNPs were not in the coding regions of the genes but were involved in regulation.
you need the SNPs to turn on the transcription factors.

why are there low odds ratio in complex diseases
because they are transcription factors and not protein coding sequences
most SNPs found by GWAs are where

disease associated variants are concentrated in which sites?
most SNPs found by GWAs are in regulatory sites. not protein coding sites

regulatory sites
there are transcription factors that work on other transcription factors, thus proof that mutation in transcription factor can cause a complex disease
ex. a single mutation in a transcription factor can cause diabetes.
thus transcription factors can affect different genes
why are rare variants stronger?
they are found in protein coding sequences.
If you alter an AA in a protein coding gene, it's gonna strongly affect the phenotype.
the cost of sequencing has declined that allowed these rare variant studies to be done
rare variant hypothesis: common diseases is due to aggregate of multiple different rare variants rather than only common variants, what does that mean?
100ppl with diabetes I,
1 person might have a mutation in exon 1, another a mutation in exon 2. and another exon 5...
each person has a diiferent mutation, but still diabetes I.
Each is rare, but together these rare variants could account for a signficant population risk for that gene. it can explain common diseases
A susceptibilty gene may contain many individual uncommon variants, each of which have almost complete penetrance since it is affecting the protein coding sequence. How can this explain why complex diseases are so common?
each gene mutation may be very rare, but if u look at all the rare variants of the gene it can be very common.

each gene mutation is very rare, you wouldnt be able to pick it up with GWAS because it only does common SNPs, but if u sequence that protein in ppl u would find rare variants at different exons.

Thus this is how rare variants can explain common diseases.
GWAS will not identify rare variants in most cases, what is required
sequencing the candidate gene is required.
selecting the candidate gene is based on prior knowledge.

exome sequencing is now affordable and allows scientists to look for rare mutations in common diseases.
as with using exome sequencing in Mendelian diseases, using become sequencing is complicated due to the large number of SNPs each person has.
computer generated methods must be used to identify the variant and genes involved in the common disease.
most of the rare variants identified have been found to be causative, that is
they affect gene expression levels or adversely impact the protein's function
2 approaches to identifying rare variants in common diseases:
-sequencing relatives of common descent(likely to have the same causes of diseases)

-by looking at ppl with with high activity or low activity, and see which SNPs are different because most SNPs will prob be the same except the rare ones.
what was found by looking at X-chromosome coding exons of X-linked mental retardation(XLMR)?
they found 9 genes that were causing mental retardation, confirming the power of identifying rare variants.
rare coding variants were also found in Pts with Late Onset Alzheimer's disease.
they found a rare variant in the gene Phospholipase D3.(decreased PLD3, increased amyloid-beta precursor protein.)

Studies in additional Alzheimer families found variant increased the risk of Late Onset Alzheimer Disease by two fold
what role did phospholipase D3 (PLD3) play?
it processes(lowers) the amyloid-beta precursor protein.

-PLD3 lower in Late Onset Alzheimer Disease brains than control brains
-decreased PLD3, increased amyloid-beta precursor protein.
how is Zn involved in insulin production?
ZnT8 transporter. Zn is stored with insulin, 6 insulin molecules are held together by Zn molecules.

If you have decreased Zn, you will have decreased insulin levels.
how does the loss of function mutation in SLC30A8 protect against Type II diabetes?
A gene that encodes for islet Zn, that is responsible for the carrying insulin. Thus less Zn, means less insulin. But in contrast, they found that a loss-of function mutation in that of SCL30A8 haploinsufficiency, (gene for encoding the Zn proteins) protects against Type II diabetes, suggesting that ZnT8 inhibition as a therapeutic stratgey in Type II diabetes.
Most likely both common and rare variants are involved in common diseases.

That common variants are involved in transcription factors and other regulatory elements

and the rare variants are involved in protein coding, DNA promoters.
But to study these variants, we need a large number of Pts
common SNPs affect regulatory elements

rare SNPs are in the protein coding regions
Common disease phenotypes may involve the additive contribution of hundreds of SNPs, each regulating a series of biochemical traits that effect the disease phenotype
you can carry a number of alleles for a disease but unless you have a certain amt, u wont get the disease.
you are perfectly fine, until you become overweight, then boom you have diabetes.
you need a certain number of alleles of SNPs in different genes before the disease phenotype is observed, this is called the threshold model.

A certain combination of (common and rare variants) environmental factors is needed in order for a person to be affected with a multifactorial condition.

The genetic and environmental factors add together and when they reach the threshold level, it causes a person to be affected.
when u have a combination of diff enzyme activities in a pathway, and u have differences in enzymes caused by SNPs, in combination, sometimes you will produce the phenotype, other times it wont.
in obesity, which gene do u want to knock out to stay skinny?

there is a gene FTO, it has the highest odds ratio, there is a SNP in the intron.
the SNP in the intron is not affecting this gene, but it is affecting another gene called IRX3.

If you knock out IRX3, you stay skinny
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