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In the context of pharmacogenomics, whole genome sequencing provides apowerful approach for identifying correlations between response variability tospecific drugs and genomic polymorphisms in a population, in an unbiasedmanner. In this study, we employed whole genome sequencing of DNA samples frompatients showing extreme response (n=72) and non-response (n=27) to theantiepileptic drug levetiracetam, in order to identify genomic variants thatunderlie response to the drug. Although no common SNP (MAF>5%) crossed theconventional genome-wide significance threshold of 5e-8, we found commonpolymorphisms in genes SPNS3, HDC, MDGA2, NSG1 and RASGEF1C, which collectivelypredict clinical response to levetiracetam in our cohort with ~91% predictiveaccuracy. Among these genes, HDC, NSG1, MDGA2 and RASGEF1C are potentiallyimplicated in synaptic neurotransmission, while SPNS3 is an atypical solutecarrier transporter homologous to SV2A, the known molecular target oflevetiracetam. Furthermore, we performed gene- and pathway-based statisticalanalysis on sets of rare and low-frequency variants (MAF<5%) and we identifiedassociations between the following genes or pathways and response tolevetiracetam: a) genes PRKCB and DLG2, which are involved in glutamatergicneurotransmission, a known target of anticonvulsants, including levetiracetam;b) genes FILIP1 and SEMA6D, which are involved in axon guidance and modellingof neural connections; and c) pathways with a role in synapticneurotransmission, such as WNT5A-dependent internalization of FZD4 anddisinhibition of SNARE formation. In summary, our approach to utilise wholegenome sequencing on subjects with extreme response phenotypes is a feasibleroute to generate plausible hypotheses for investigating the genetic factorsunderlying drug response variability in cases of pharmaco-resistant epilepsy.

Whole genome sequencing identifies putative associations between genomic polymorphisms and clinical response to the antiepileptic drug levetiracetam