During the past years, genome-wide association studies have been extremely successful in identifying genomic regions underlying various human diseases and quantitative phenotypes. However, any one associated genomic region can harbour hundreds or even thousands of correlated genetic variants.
The main aim of M.Sc., Christian Benner’s thesis entitled "FINEMAP: a Statistical Method for Identifying Causal Genetic Variants” was to develop more efficient statistical tools to gain better understanding of the underlying biological mechanisms that lead to these associations. The thesis presents the development of the FINEMAP software for fine-mapping causal variants in the associated genomic regions.
His doctoral dissertation will be publicly examined on Friday, 18 January, with the permission of the Faculty of Medicine of the University of Helsinki.
Christian graduated from the University of Helsinki in 2013, with a masters in Bayesian Statistics. Thanks to Jukka Corander, the supervisor of his master’s thesis, who introduced Christian to the genomics research done at FIMM, Christian made the decision to start working with his PhD thesis project under the supervision of FIMM Group Leaders Matti Pirinen and Samuli Ripatti.
The main goal of the thesis became soon clear.
The next major challenge in genetics research is to understand the biological processes behind the identified statistical associations. Better understanding of the biology underlying the associated genomic regions is needed to identify genes that could become drug targets for the development of new therapeutic interventions.
- Christian Benner
The thesis consists of three publications, two of which have already been published.
In the first publication of the thesis, Christian focused on solving issues related to computationally expensive exhaustive search strategy of existing fine-mapping methods. He implemented a Bayesian regression model and an ultrafast stochastic search algorithm in the FINEMAP software. The simulations showed that FINEMAP achieves much higher computational efficiency without sacrificing any accuracy compared to the previously available methods.
In the second publication, Christian looked at the effect of the linkage disequilibrium (LD) information on the accuracy of the fine-mapping results. He concluded that LD estimates need to be chosen more carefully than the researchers have previously realised to avoid bias.
This finding has important consequences for the application of all fine-mapping methods using GWAS results from GWAS consortia in which accurate LD estimates from each participating study are typically not available.
In the last part of the thesis work, Christian implemented in FINEMAP an approach for estimating how much phenotypic variation can be explained by the causal variants. For most phenotypes, accounting for all the genomic variation still provides higher heritability estimates than if only the causal variants are used. However, his results indicate that upcoming large data sets will provide new opportunities for getting a more exact variant-level picture of regional genetic architecture.
FINEMAP has users from all the major universities working on large-scale genomic data. The fact that so many research groups have already adopted FINEMAP in their projects shows that the community finds it a useful tool. In collaboration with Helsinki Innovation Services, the software has been commercialised and licences to the software are available for biotech and pharmaceutical companies.
Christian will continue working at FIMM at least until the summer to finish his ongoing work and to settle his next career move.
The public examination of Christian Benner’s doctoral dissertation will take place on 18 January at 14:00 in Biomedicum Helsinki, Lecture Hall 3, Haartmaninkatu 8. The thesis has been supervised by FIMM Group Leader, Academy Research Fellow Matti Pirinen (University of Helsinki) and FIMM-EMBL Group Leader, Professor Samuli Ripatti (University of Helsinki). Associate Professor Zoltán Kutalik (University of Lausanne, Switzerland) will serve as the opponent and Professor Samuli Ripatti as the custos. The dissertation is also available in an electronic form.