WEHI PhD Completion Seminar hosted by Professor Melanie Bahlo
Karen Oliver
PhD Student – Bahlo Laboratory, Population Health & Immunity division – Healthy Development & Ageing Theme, WEHI
Understanding epilepsy genetic risk: integrating common and rare genetic variation
L2 Seminar Room, Melbourne Brain Centre – Austin Health, 245 Burgundy Street, Austin Health, Heidelberg
Password 635895
Including Q&A session
The epilepsies are a group of neurological disorders affecting up to 4% of people during their lifetime. Genetics has long been known to play a role in epilepsy aetiology and we now know that both rare (monogenic) and common (polygenic) variation contribute to genetic risk.
Experimental approaches for detecting rare versus common genetic variants are quite distinct and, therefore, typically studied independently. The advent of whole -exome and -genome sequencing has seen the number of monogenic epilepsy gene discoveries rapidly increase whilst large international case-control genome-wide association studies (GWAS) continue to identify common epilepsy risk variants. Using this latter genetic information, it is now possible to quantitate the contribution of common epilepsy risk variants in individuals by calculating an epilepsy polygenic risk score (PRS). The over-arching aim of this study has been to bridge the “rare variant – common variant” divide and explore their potential genetic interplay in families with epilepsy.
In this study we show that epilepsy PRS is enriched in patients with a positive family history for epilepsy compared to those without. This is particularly interesting because families with epilepsy have previously been targeted for rare variant/monogenic discoveries and here we provide support for common genetic variation playing a role in the familial aggregation of epilepsy. We explore whether the role being played by epilepsy PRS is disease modifying. We do this by studying clinically heterogenous families – many segregating a known pathogenic rare variant with reduced penetrance – and show that epilepsy PRS is associated with epilepsy outcome. To our knowledge, this provides the first support for common genetic background modifying the clinical expression of rare pathogenic variants in the epilepsies.
All welcome!
