Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin

Isabelle Boothman; Lisa M Clayton; Mark McCormack; Alexandra McKibben Driscoll; Remi Stevelink; Patrick Moloney; Roland Krause; Wolfram S Kunz; Sarah Diehl; Terence J O'Brien; Graeme J Sills; Gerrit-Jan de Haan; Federico Zara; Bobby P Koeleman; Chantal Depondt; Anthony G Marson; Hreinn Stefansson; Kari Stefansson; John Craig; Michael R Johnson; Pasquale Striano; Holger Lerche; Simon J Furney; Norman Delanty; Consortium EpiPGX; Sanjay M Sisodiya; Gianpiero L Cavalleri

doi:10.3389/fnins.2023.1156362

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin

Front Neurosci. 2023 Sep 8:17:1156362. doi: 10.3389/fnins.2023.1156362. eCollection 2023.

Authors

Isabelle Boothman^{1

2

3}, Lisa M Clayton^{4

5}, Mark McCormack¹, Alexandra McKibben Driscoll¹, Remi Stevelink⁶, Patrick Moloney¹, Roland Krause⁷, Wolfram S Kunz⁸, Sarah Diehl⁷, Terence J O'Brien⁹, Graeme J Sills¹⁰, Gerrit-Jan de Haan¹¹, Federico Zara^{12

13}, Bobby P Koeleman⁶, Chantal Depondt¹⁴, Anthony G Marson¹⁵, Hreinn Stefansson¹⁶, Kari Stefansson¹⁶, John Craig¹⁷, Michael R Johnson¹⁸, Pasquale Striano^{12

13}, Holger Lerche¹⁹, Simon J Furney²⁰, Norman Delanty¹; Consortium EpiPGX; Sanjay M Sisodiya^{4

5}, Gianpiero L Cavalleri^{1

2

3}

Collaborators

Affiliations

¹ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
² The SFI Futureneuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
³ The SFI Centre for Research Training in Genomics Data Science, Galway, Ireland.
⁴ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁵ Chalfont Centre for Epilepsy, Bucks, United Kingdom.
⁶ Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
⁸ Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Bonn, Germany.
⁹ Departments of Neuroscience and Neurology, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, VIC, Australia.
¹⁰ School of Life Sciences, University of Glasgow, Glasgow, United Kingdom.
¹¹ Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands.
¹² "IRCCS"G. Gaslini" Institute, Genova, Italy.
¹³ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.
¹⁴ Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
¹⁵ Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
¹⁶ deCODE Genetics, Reykjavik, Iceland.
¹⁷ Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom.
¹⁸ Division of Brain Sciences, Imperial College Faculty of Medicine, London, United Kingdom.
¹⁹ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁰ Genomic Oncology Research Group, Deptartment of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.

Abstract

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.

Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.

Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.

Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Keywords: adverse drug reaction; epilepsy; genome wide association study; polygenic risk score; retina.

Copyright © 2023 Boothman, Clayton, McCormack, Driscoll, Stevelink, Moloney, Krause, Kunz, Diehl, O’Brien, Sills, de Haan, Zara, Koeleman, Depondt, Marson, Stefansson, Stefansson, Craig, Johnson, Striano, Lerche, Furney, Delanty, Consortium, Sisodiya and Cavalleri.