In the shade of the furnaces. The EuroEPINOMICS consortium met for the first data analysis meeting at the Luxembourg Center for System Biomedicine (LCSB) from July 5-7th, 2012. What was intended to be a small, private meeting on data analysis eventually turned into a medium-size consortium meeting with lively, sometimes revealing discussions. Belval is a campus in transition, a large steel mill that is currently transformed into the new campus of the University of Luxembourg. The LCSB people are the “first kids on the block”. The atmosphere of Belval is a mixture of industrial romance and pioneer spirit, the ideal backdrop for re-considering our current approaches to deciphering the genetics of the epilepsies.
The results. The CoGIE and RES subprojects have generated sequence data already exceeding the proverbial 1000 exomes including pioneer projects using whole genome sequence (WGS) for WGS-based family analysis. Exome data has already revealed promising leads, and separate emails with more information will be sent to consortium members in the next weeks. The genetic presentations were framed by additional talks by LCSB system biologists, highlighting the fact that system biology approaches complementing genetic analysis are a force to be reckoned with.
What has changed in the last four months. The recent months have witnessed the publication of several high-impact studies exploring the genetic architecture of autism using trio-based exome sequencing. The results for autism are depressing: de novo mutations are frequent in affected and unaffected individuals and distinguishing between benign and pathological variation is virtually impossible. Only four genes have been found to be mutated twice in several hundred trios with autism, indicating that genetic heterogeneity is more complex than expected. We are thrown back into an era where association is needed to guide us. And association means large numbers. The group of Shawn Purcell has attempted to estimate the samples needed for a sufficiently powered analysis of exome data. The answer is: at least 10,000 cases and controls. Either you look at monogenic disorders or you need 10,000 samples. Don’t compromise.
The meeting of the 1,000, but not 10,000 exomes. The Sanger exome project was initially intended to solve the genetic architecture of Childhood Absence Epilepsy with 500-800 exomes. This concept needs to be revised in light of the recent findings and power calculations; a reasonable study on complex genetic seizure disorders will require a coordinated international effort to provide sufficient sample sizes.
Don’t give up. If a thorough approach to solving the genetic complexity is not in the immediate future, the question arises what else exome data can be used for. The focus will turn to monogenic epilepsies, including both the classical rare epilepsies in the RES project as well as monogenic variants of common epilepsies. Exome data has the potential to uncover unknown or unexpected monogenic disorders and might already be more economically feasible than two candidate gene screens. Therefore, even in exome samples underpowered for complex genomics, surprises and confirmation of existing candidates can be expected. In summary, once you have accepted the sad truth that a systematic analysis is light years away, be surprised by some genes that beat the odds.
Program or be programmed. The Luxembourg meeting turned out much larger than expected, suggesting a rising interest in bioinformatics. Author Douglas Rushkoff has suggested that in the near future, you either program or you will be programmed. The attendance of this meeting shows that the European epilepsy genetics community has already received his message. Scientists and clinicians are becoming increasingly interested in how data is analyzed, not only in the final results. The offer of the Cologne Center of Genomics’ to host a hands-on exome workshop for young scientists is therefore a further step into the same direction, taking full advantage of the networking capacities of EuroEPINOMICS.
All we need. The entire consortium would like to thank the LCSB staff again for hosting this meeting, which -in my opinion- turned out be one of the most intellectually stimulating meetings in the field in the last few years. Due to the ongoing reconstruction efforts Belval will look completely different when we meet in Luxembourg next time. Therefore, we have captured some impressions of the Belval and its furnaces on Flickr.
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