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

TL;DR

This study uses whole genome sequencing of extreme responders and non-responders to levetiracetam to identify genetic variants associated with drug response, revealing potential genetic markers and pathways involved in epilepsy treatment variability.

Contribution

It demonstrates the feasibility of using whole genome sequencing on extreme phenotypes to discover genetic factors influencing drug response in epilepsy.

Findings

Common polymorphisms in genes SPNS3, HDC, MDGA2, NSG1, RASGEF1C predict response with ~91% accuracy.

Associations between rare variants in PRKCB, DLG2, FILIP1, SEMA6D and drug response.

Pathways involved in synaptic neurotransmission and neural connectivity are linked to levetiracetam response.

Abstract

In the context of pharmacogenomics, whole genome sequencing provides a powerful approach for identifying correlations between response variability to specific drugs and genomic polymorphisms in a population, in an unbiased manner. In this study, we employed whole genome sequencing of DNA samples from patients showing extreme response (n=72) and non-response (n=27) to the antiepileptic drug levetiracetam, in order to identify genomic variants that underlie response to the drug. Although no common SNP (MAF>5%) crossed the conventional genome-wide significance threshold of 5e-8, we found common polymorphisms in genes SPNS3, HDC, MDGA2, NSG1 and RASGEF1C, which collectively predict clinical response to levetiracetam in our cohort with ~91% predictive accuracy. Among these genes, HDC, NSG1, MDGA2 and RASGEF1C are potentially implicated in synaptic neurotransmission, while SPNS3 is an atypical solute carrier transporter homologous to SV2A, the known molecular target of levetiracetam. Furthermore, we performed gene- and pathway-based statistical analysis on sets of rare and low-frequency variants (MAF<5%) and we identified associations between the following genes or pathways and response to levetiracetam: a) genes PRKCB and DLG2, which are involved in glutamatergic neurotransmission, a known target of anticonvulsants, including levetiracetam; b) genes FILIP1 and SEMA6D, which are involved in axon guidance and modelling of neural connections; and c) pathways with a role in synaptic neurotransmission, such as WNT5A-dependent internalization of FZD4 and disinhibition of SNARE formation. In summary, our approach to utilise whole genome sequencing on subjects with extreme response phenotypes is a feasible route to generate plausible hypotheses for investigating the genetic factors underlying drug response variability in cases of pharmaco-resistant epilepsy.