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Friday, February 6, 2009

Keynote Speaker: Kari Sefansson, deCODE Genetics - “Common/Complex traits with emphasis on disease”

Sounds like Sean Connery!

Basic assumption is that information is the basic unit of life – and the genome is the carrier. Creating database where we can start decoding that information – and have had some success, including to find the genes for the love of complex crossword puzzles. (-:

Traits range in complexity from simple mendelian all the way to really complex genotypes and phenotypes, which are often involved in diseases. One thing to keep in mind is that they also have geographical traits.

First example: melanoma. Very different genes (for light hair and skin) occur in the population varrying by location - people in iceland don't have problems carrying this gene, but those in spain would!

Second example: Genetic risk of atrial fibrillation is genetic risk of cardiogenic stroke. About 30% of stroke is indeterminate origin, but a significant proportion is associated with several genetic traits. [insert much statistics here!]

Third example: Thyroid Cancer – (published today?). Incidence is increasing of late. If it's caught early, it has a very good prognosis. It has a very large familial component. Did a genome association in iceland, identified 1100 individuals, and had genotypes 580 of them. Pulled out 2 significant loci (independent), and they associated with two forms of thyroid cancer. [more statistics too fast to make notes...] Individuals with both genes have 5.7X increase in risk. (Multiplicative model.) The two loci also have diffences in clinical presentations. Candidate for first is FOXE(TTF2) transcription factor. Second is NKX2-1(TTF1). Apparently these gene(s?) regulate Thyroid Stimulating Hormone... so there may be an interesting mechanism.

Where are we now when it comes to discoveries of sequence varieties that code for genetic components of complex disease? There seems to be a significant amount of undiscovered diseases. Most of the ones that have been discovered have risk factors over 5%.... [not sure if that's right] Bottom line is that the detection limits are such that we can't find the really low variants with lower risk factors.

There may be a large contribution from rare variants with large effects
There may be a large contribution from rare variants with small or modes effects.
[one more.. not fast enough]

Started deCODE based on family based methods, and now have returned to it. Concept of Surrogate Parenthood – surrogates work as well as natural parents for phasing of proband. To get down to all traits with 2% of variants, they would only need to sequence ~2000 people. [Daniel says there are only 400,000 people in Iceland].

Have also noted genes where the risk factor is different between maternally and paternally passed genes.

Prostate cancer: have shown that there are 8 genes that have a cumulative risk factor. Important for treatment and preventative care.

End by pointing out that in all of the common disease, it is a disease where there are both environmental and genetic components. How do they interact? How do they fit into our debate (nature vs. Nurture).

Published on nicotine dependence and lung cancer last year. In iceland, it's purely environmental – only smokers in iceland develop cancer (14%). Discovered a sequence variant that makes you more likely to smoke more because you're more likely to crave the nicotine.. where is the line between nature and nurture, then? To solve this problem, you need to understand the brain – to understand the behaviours that make us susceptible to environmental diseases.



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