GWAS applications

Question 1

What are the three things GWAS achieves

Answer 1

Understand about the genetic basis of human disease, from a purely basic science point of view.

Understand the mechanism behind a disease, and understand precisely how the biology has gone wrong, in the hope that this may help us invent cures or treatments

Predict who might be susceptable to a particular disorder. Perhaps allowing early interventions, enhanced screening, or environmental interventions we can take to help there people.

Question 2

In early GWAS studies, what have we discovred about Type 1 diabetes

Answer 2

Identified DQbeta-1, accounts for 50% of the heritability indeitfied so far in T1D

Identified variants with large, but not massive effects upstream of the insulin gene itself, as well as variants in a phosphatase called PTPN22.

Question 3

T1D: Describe the remaining variants

Answer 3

The remaining varitants were of much smaller effect sizes and were located near genes connected to the immune system (both innate and adaptive). THus, the effect sizes formed a ‘J-shaped’ curve, with a small number of large effect variants, and a large number of small effect variants, something seen for many conditions

Question 4

T1D: WHat is DQbeta-1 part of?

Answer 4

MHC complex that presents antigens to T-cells so that can distinguish self from non-self. As T1D is an autoimmune disease, makes sense.

Question 5

T1D: What was not clear but now is

Answer 5

Variants of the insulin promotor, its was not clear how thats connected to why T-cells kills beta-cells. This became cleaered when it was realised that the variants reduce expression of insulin not in the pancrease, but in the thymus.

Question 6

What is the thymus

Answer 6

Organ where T-cells mature.
T-cells learn to distunguish self from non-se;f.

Question 7

T-cells

Answer 7

When first born, T-cells have a more or less randon reactivity. These new T-cells are passed through the thymic medulla, which is home to medullary thymic epithelial cell (mTEC). These cells are special

Question 8

medullary thymic epithelial cell (mTEC).

Answer 8

These cells are special because thye express a transcription factor called AIRE, which activates the expression of every protein in the genome. The mTECs present these protein to the immature T-cells.

Question 9

What happens to T-cells when present proteins by mTEC

Answer 9

Any T-cell that recognises an antigen present by an mTEC is activated, and this triggers apoptosis, removing the self-reactive T-cell

Question 10

WHat happens to individuals with mutation in DQbeta-1

Answer 10

They dont efficiently present insulin on their mTECs.

Question 11

WHat happens to individuals with mutation in insulin promotors

Answer 11

Those with mutant insulin promotors don’t efficiently produce insulin in the mTECs to be presented.

Question 12

WHat us PTPN22 and other implicated genes invovled in?

Answer 12

In ensuring the T-cells activated in the thymus undergo apoptosis rather than proliferation.

Question 13

IF this system isnt strong enough to activate T-cells in thymus, how come it activates them in pancrease?

Answer 13

The insulin reactive t-cells ae only activated under already inflammatory conditions, triggered by the innate immune system. Thus, something like an infection is necessary to trigger the activation of insulin reactive t-cells and the destruction of the pancreastic beta cells.

Question 14

T1D: whats currenly underway?

Answer 14

Drug traisl to find ways of counteracting the anti-apoptotic decision point in the thymus. Thus in diabetes GWAS results have lead to directly to treatment possibilites.

Question 15

Risk of developing breast cancer

Answer 15

Using results of GWAS study to predict which individuals might be at high risk

For this we dont need to know what any of the associated alleles or genes are doing.

Question 16

Breast cancer screening

Answer 16

50 - 70 - this age range is a compromise.

Question 17

Problem with breast cancer screening

Answer 17

If you screen people who are at low risk, you will likely end up over treating people.

Because at a sufficiently low risk, a positive result is more likely to be a flase positive than a real result, however accurate test is.

Question 18

What else might be found in breast cancer screening?

Answer 18

In cancer screen, it also means you might find low risk neoplasm that probably would not ever have developed into anything harmful.

Question 19

How many lives does screening save? Whats the problem?

Answer 19

1300. But also leads to 4000 unneccessary treatments.

Treatments are often highly unpleasant. But on other hand, if you are at high risk for breast cancer,such as those with strong family history, 50 might be too late to catch tumour early enough.